HCSGD entry for TP53

1. General information

Official gene symbol	TP53
Entrez ID	7157
Gene full name	tumor protein p53
Other gene symbols	BCC7 LFS1 P53 TRP53
Links to Entrez Gene	Links to Entrez Gene

2. Neighbors in the network

3. Gene ontology annotation

GO ID	GO term	Evidence	Category
GO:0000060	Protein import into nucleus, translocation	IEA	biological_process
GO:0000122	Negative regulation of transcription from RNA polymerase II promoter	IBA IDA IEA ISS	biological_process
GO:0000733	DNA strand renaturation	IDA	biological_process
GO:0000785	Chromatin	IBA	cellular_component
GO:0000790	Nuclear chromatin	IDA	cellular_component
GO:0000979	RNA polymerase II core promoter sequence-specific DNA binding	IEA	molecular_function
GO:0001077	RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription	IEA	molecular_function
GO:0001085	RNA polymerase II transcription factor binding	IPI	molecular_function
GO:0001228	RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription	IDA	molecular_function
GO:0001701	In utero embryonic development	IEA	biological_process
GO:0001756	Somitogenesis	IEA	biological_process
GO:0001836	Release of cytochrome c from mitochondria	IEA	biological_process
GO:0002020	Protease binding	IPI	molecular_function
GO:0002039	P53 binding	IBA	molecular_function
GO:0002309	T cell proliferation involved in immune response	IEA	biological_process
GO:0002326	B cell lineage commitment	IEA	biological_process
GO:0002360	T cell lineage commitment	IEA	biological_process
GO:0002931	Response to ischemia	IEA	biological_process
GO:0003677	DNA binding	IMP	molecular_function
GO:0003682	Chromatin binding	IDA IEA	molecular_function
GO:0003684	Damaged DNA binding	IBA	molecular_function
GO:0003700	Sequence-specific DNA binding transcription factor activity	IDA IEA	molecular_function
GO:0005507	Copper ion binding	IDA	molecular_function
GO:0005515	Protein binding	IPI	molecular_function
GO:0005524	ATP binding	IDA	molecular_function
GO:0005634	Nucleus	IDA IEA	cellular_component
GO:0005654	Nucleoplasm	IDA TAS	cellular_component
GO:0005657	Replication fork	IBA IEA	cellular_component
GO:0005669	Transcription factor TFIID complex	IDA	cellular_component
GO:0005730	Nucleolus	IDA	cellular_component
GO:0005737	Cytoplasm	IDA IEA	cellular_component
GO:0005739	Mitochondrion	IDA IEA	cellular_component
GO:0005759	Mitochondrial matrix	IEA	cellular_component
GO:0005783	Endoplasmic reticulum	IEA	cellular_component
GO:0005829	Cytosol	IBA IDA IEA	cellular_component
GO:0006284	Base-excision repair	TAS	biological_process
GO:0006289	Nucleotide-excision repair	IMP	biological_process
GO:0006302	Double-strand break repair	IEA	biological_process
GO:0006351	Transcription, DNA-templated	IEA	biological_process
GO:0006355	Regulation of transcription, DNA-templated	IDA	biological_process
GO:0006366	Transcription from RNA polymerase II promoter	IDA	biological_process
GO:0006461	Protein complex assembly	IDA	biological_process
GO:0006915	Apoptotic process	IEA	biological_process
GO:0006974	Cellular response to DNA damage stimulus	IDA	biological_process
GO:0006977	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest	IEA TAS	biological_process
GO:0006978	DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator	IMP	biological_process
GO:0006979	Response to oxidative stress	IEA	biological_process
GO:0006983	ER overload response	IDA	biological_process
GO:0007049	Cell cycle	IEA	biological_process
GO:0007050	Cell cycle arrest	IDA IMP	biological_process
GO:0007179	Transforming growth factor beta receptor signaling pathway	IEA	biological_process
GO:0007265	Ras protein signal transduction	IEP	biological_process
GO:0007275	Multicellular organismal development	IMP	biological_process
GO:0007369	Gastrulation	IEA	biological_process
GO:0007406	Negative regulation of neuroblast proliferation	IEA	biological_process
GO:0007417	Central nervous system development	IEA	biological_process
GO:0007569	Cell aging	IEA IMP	biological_process
GO:0007596	Blood coagulation	TAS	biological_process
GO:0008104	Protein localization	IDA	biological_process
GO:0008134	Transcription factor binding	IPI	molecular_function
GO:0008156	Negative regulation of DNA replication	IEA	biological_process
GO:0008270	Zinc ion binding	TAS	molecular_function
GO:0008283	Cell proliferation	TAS	biological_process
GO:0008285	Negative regulation of cell proliferation	ISS	biological_process
GO:0008340	Determination of adult lifespan	IEA ISS	biological_process
GO:0009303	RRNA transcription	IEA	biological_process
GO:0009651	Response to salt stress	IEA	biological_process
GO:0010165	Response to X-ray	IBA IEA	biological_process
GO:0010332	Response to gamma radiation	IEA IMP	biological_process
GO:0010666	Positive regulation of cardiac muscle cell apoptotic process	IEA	biological_process
GO:0016032	Viral process	IEA	biological_process
GO:0016363	Nuclear matrix	IDA	cellular_component
GO:0016604	Nuclear body	IDA	cellular_component
GO:0016605	PML body	IDA	cellular_component
GO:0019899	Enzyme binding	IPI	molecular_function
GO:0019901	Protein kinase binding	IPI	molecular_function
GO:0030154	Cell differentiation	TAS	biological_process
GO:0030308	Negative regulation of cell growth	IMP	biological_process
GO:0030330	DNA damage response, signal transduction by p53 class mediator	IDA IMP	biological_process
GO:0030512	Negative regulation of transforming growth factor beta receptor signaling pathway	IEA	biological_process
GO:0030971	Receptor tyrosine kinase binding	IPI	molecular_function
GO:0031065	Positive regulation of histone deacetylation	IBA IEA	biological_process
GO:0031497	Chromatin assembly	IDA	biological_process
GO:0031571	Mitotic G1 DNA damage checkpoint	IMP	biological_process
GO:0031625	Ubiquitin protein ligase binding	IPI	molecular_function
GO:0032461	Positive regulation of protein oligomerization	IDA	biological_process
GO:0033077	T cell differentiation in thymus	IEA	biological_process
GO:0034103	Regulation of tissue remodeling	IEA	biological_process
GO:0034613	Cellular protein localization	IDA	biological_process
GO:0034644	Cellular response to UV	IBA IEA	biological_process
GO:0035033	Histone deacetylase regulator activity	IEA	molecular_function
GO:0035035	Histone acetyltransferase binding	IPI	molecular_function
GO:0035264	Multicellular organism growth	IEA	biological_process
GO:0035690	Cellular response to drug	IEP	biological_process
GO:0042149	Cellular response to glucose starvation	IDA	biological_process
GO:0042493	Response to drug	IEA	biological_process
GO:0042771	Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IDA IEA	biological_process
GO:0042802	Identical protein binding	IPI	molecular_function
GO:0042981	Regulation of apoptotic process	IDA	biological_process
GO:0043065	Positive regulation of apoptotic process	IDA	biological_process
GO:0043066	Negative regulation of apoptotic process	IDA IEA	biological_process
GO:0043234	Protein complex	IDA	cellular_component
GO:0043525	Positive regulation of neuron apoptotic process	IBA IEA	biological_process
GO:0044212	Transcription regulatory region DNA binding	IDA IEA	molecular_function
GO:0045892	Negative regulation of transcription, DNA-templated	ISS	biological_process
GO:0045893	Positive regulation of transcription, DNA-templated	IDA IMP	biological_process
GO:0045944	Positive regulation of transcription from RNA polymerase II promoter	IDA IGI IMP	biological_process
GO:0046677	Response to antibiotic	IEP	biological_process
GO:0046872	Metal ion binding	IEA	molecular_function
GO:0046902	Regulation of mitochondrial membrane permeability	TAS	biological_process
GO:0046982	Protein heterodimerization activity	IPI	molecular_function
GO:0047485	Protein N-terminus binding	IPI	molecular_function
GO:0048147	Negative regulation of fibroblast proliferation	IEA IMP	biological_process
GO:0048568	Embryonic organ development	IEA	biological_process
GO:0050731	Positive regulation of peptidyl-tyrosine phosphorylation	IEA ISS	biological_process
GO:0051087	Chaperone binding	IPI	molecular_function
GO:0051097	Negative regulation of helicase activity	TAS	biological_process
GO:0051262	Protein tetramerization	TAS	biological_process
GO:0051276	Chromosome organization	IEA	biological_process
GO:0051402	Neuron apoptotic process	IEA	biological_process
GO:0051721	Protein phosphatase 2A binding	IPI	molecular_function
GO:0070245	Positive regulation of thymocyte apoptotic process	IEA ISS	biological_process
GO:0071158	Positive regulation of cell cycle arrest	IMP	biological_process
GO:0071456	Cellular response to hypoxia	IEP	biological_process
GO:0071479	Cellular response to ionizing radiation	IEA IMP	biological_process
GO:0071850	Mitotic cell cycle arrest	IEA	biological_process
GO:0072332	Intrinsic apoptotic signaling pathway by p53 class mediator	IMP	biological_process
GO:0090200	Positive regulation of release of cytochrome c from mitochondria	IDA	biological_process
GO:0090343	Positive regulation of cell aging	IEA	biological_process
GO:0090399	Replicative senescence	IMP	biological_process
GO:0090403	Oxidative stress-induced premature senescence	IMP	biological_process
GO:0097193	Intrinsic apoptotic signaling pathway	TAS	biological_process
GO:0097252	Oligodendrocyte apoptotic process	IDA	biological_process
GO:0097371	MDM2/MDM4 family protein binding	IEA	molecular_function
GO:1901525	Negative regulation of macromitophagy	IEA	biological_process
GO:1902108	Regulation of mitochondrial membrane permeability involved in apoptotic process	IEA	biological_process
GO:2000378	Negative regulation of reactive oxygen species metabolic process	IEA	biological_process
GO:2000379	Positive regulation of reactive oxygen species metabolic process	IMP	biological_process
GO:2001244	Positive regulation of intrinsic apoptotic signaling pathway	IMP	biological_process

Entries Per Page

Displaying Page of

4. Expression levels in datasets

Meta-analysis result

p-value up	p-value down	FDR up	FDR down
0.9545231754	0.0066859390	0.9999902473	0.1642558769

Individual experiment result
( "-" represent NA in the specific microarray platform )

Data source	Up or down	Log fold change
GSE11954	Down	-0.4076498173
GSE13712_SHEAR	Up	0.0493070005
GSE13712_STATIC	Down	-0.4378968375
GSE19018	Up	0.2516922550
GSE19899_A1	Down	-0.8603389737
GSE19899_A2	Down	-0.2589848485
PubMed_21979375_A1	Down	-1.6968082673
PubMed_21979375_A2	Down	-1.4053414584
GSE35957	Down	-0.1592541824
GSE36640	Down	-0.9861981521
GSE54402	Down	-0.6062087234
GSE9593	Up	0.2514695160
GSE43922	Down	-0.9721082916
GSE24585	Down	-0.1698012828
GSE37065	Down	-0.6024336045
GSE28863_A1	Up	0.2438989314
GSE28863_A2	Up	0.0695142304
GSE28863_A3	Up	0.0778967746
GSE28863_A4	Up	0.0302515539
GSE48662	Down	-0.1032762382

5. Regulation relationships with compounds/drugs/microRNAs

Compounds

Compound	Target	Confidence score	Uniprot
CHEMBL584299	CHEMBL4096	9	P04637
CHEMBL567636	CHEMBL4096	9	P04637
CHEMBL583626	CHEMBL4096	9	P04637
CHEMBL567403	CHEMBL4096	9	P04637
CHEMBL578457	CHEMBL4096	9	P04637
CHEMBL584512	CHEMBL4096	9	P04637
CHEMBL578457	CHEMBL4096	9	P04637
CHEMBL191334	CHEMBL4096	9	P04637
CHEMBL191334	CHEMBL4096	9	P04637
CHEMBL1765371	CHEMBL4096	4	P04637

Entries Per Page

Displaying Page of

Drugs

Name	Drug	Accession number
AZD 3355	DB05404	-
1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine	DB08363	-

MicroRNAs

mirTarBase

MiRNA_name	mirBase ID	miRTarBase ID	Experiment	Support type	References (Pubmed ID)
hsa-miR-125b-5p	MIMAT0000423	MIRT000535	Luciferase reporter assay//Western blot	Functional MTI	20216554
hsa-miR-125b-5p	MIMAT0000423	MIRT000535	In situ hybridization//Luciferase reporter assay//qRT-PCR//Western blot//Reporter assay;qRT-PCR;Other	Functional MTI	19293287
hsa-miR-125b-5p	MIMAT0000423	MIRT000535	Luciferase reporter assay	Functional MTI	23497288
hsa-miR-125a-5p	MIMAT0000443	MIRT004071	Luciferase reporter assay//Northern blot//qRT-PCR//Western blot	Functional MTI	19818772
hsa-miR-25-3p	MIMAT0000081	MIRT005417	Luciferase reporter assay//qRT-PCR//Western blot	Functional MTI	20935678
hsa-miR-30d-5p	MIMAT0000245	MIRT005418	Luciferase reporter assay//qRT-PCR//Western blot	Functional MTI	20935678
hsa-miR-1285-3p	MIMAT0005876	MIRT005474	Luciferase reporter assay//qRT-PCR//Western blot	Functional MTI	20417621
hsa-miR-612	MIMAT0003280	MIRT005476	Luciferase reporter assay//qRT-PCR//Western blot	Non-Functional MTI	20417621
hsa-miR-15a-5p	MIMAT0000068	MIRT005763	Immunoblot//Luciferase reporter assay	Functional MTI	21205967
hsa-miR-16-5p	MIMAT0000069	MIRT005764	Immunoblot//Luciferase reporter assay	Functional MTI	21205967
hsa-miR-221-3p	MIMAT0000278	MIRT005785	Western blot	Non-Functional MTI	21226887
hsa-miR-222-3p	MIMAT0000279	MIRT005786	Western blot	Non-Functional MTI	21226887
hsa-miR-222-3p	MIMAT0000279	MIRT005786	CLASH	Functional MTI (Weak)	23622248
hsa-miR-214-3p	MIMAT0000271	MIRT006881	Luciferase reporter assay	Functional MTI	22927443
hsa-miR-214-3p	MIMAT0000271	MIRT006881	Reporter assay	Functional MTI	21217645
hsa-miR-10b-5p	MIMAT0000254	MIRT006923	Luciferase reporter assay	Functional MTI	23034333
hsa-miR-34a-5p	MIMAT0000255	MIRT007112	Immunohistochemistry//qRT-PCR//Immunocytochemistry	Functional MTI (Weak)	23292869
hsa-miR-608	MIMAT0003276	MIRT016154	qRT-PCR	Non-Functional MTI (Weak)	20542001
hsa-miR-605-5p	MIMAT0003273	MIRT016155	Reporter assay;qRT-PCR	Functional MTI	21217645
hsa-miR-504-5p	MIMAT0002875	MIRT016257	Reporter assay;Western blot;qRT-PCR	Functional MTI	20542001
hsa-miR-485-5p	MIMAT0002175	MIRT016616	qRT-PCR	Non-Functional MTI (Weak)	20542001
hsa-miR-27a-3p	MIMAT0000084	MIRT028744	qRT-PCR	Non-Functional MTI (Weak)	20542001
hsa-miR-454-3p	MIMAT0003885	MIRT039245	CLASH	Functional MTI (Weak)	23622248
hsa-miR-324-5p	MIMAT0000761	MIRT043041	CLASH	Functional MTI (Weak)	23622248
hsa-miR-150-5p	MIMAT0000451	MIRT052652	Luciferase reporter assay//Western blot	Functional MTI	23747308

Entries Per Page

Displaying Page of

mirRecord

MicroRNA name	mirBase ID	Target site number	MiRNA mature ID	Test method inter	MiRNA regulation site	Pubmed ID
hsa-miR-1285-3p	MIMAT0005876	1	hsa-miR-1285	{Western blot}	{overexpression by miRNA mimics tranfection}	20417621
hsa-miR-1285-3p	MIMAT0005876	2	hsa-miR-1285	{Western blot}	{overexpression by miRNA mimics tranfection}	20417621
hsa-miR-125a-5p	MIMAT0000443	NA	hsa-miR-125a-5p	{Western blot}	{overexpression by miRNA precursor transfection}	19818772
hsa-miR-380-5p	MIMAT0000734	NA	hsa-miR-380-5p	{Western blot}	{overexpression}	20871609
hsa-miR-125b-5p	MIMAT0000423	NA	hsa-miR-125b			21935352

Entries Per Page

Displaying Page of

6. Text-mining results about the gene

Gene occurances in abstracts of cellular senescence-associated articles: 1061 abstracts the gene occurs.

PubMed ID of the article	Sentenece the gene occurs
28123872	This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8+ T cells mediated through downregulation of P21WAF1, P16INK4a, and P53 expression
27824900	In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners
27803714	Within passages 4 and 8, senescent cultures exhibited typical morphological features, senescence-associated beta-galactosidase activity, increased levels of p16, and decreased levels of miR-17 and miR-21 but showed differential expression of p21, p53, and ATM dependently on the onset of cell senescence
27703600	Cholesterol Retards Senescence in Bone Marrow Mesenchymal Stem Cells by Modulating Autophagy and ROS/p53/p21Cip1/Waf1 Pathway
27703600	In the present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) of the 3rd passage displayed the senescence-associated phenotypes characterized with increased activity of SA-beta-gal, altered autophagy, and increased G1 cell cycle arrest, ROS production, and expression of p53 and p21Cip1/Waf1 compared with BMSCs of the 1st passage
27703600	Moreover, CH inhibited the production of ROS and expression of p53 and p21Cip1/Waf1 in both cellular senescence models and decreased the percentage of BMSCs in G1 cell cycle in the 3rd passage BMSCs
27703600	Our results indicate that CH not only is a structural component of cell membrane but also functionally contributes to regulating cellular senescence by modulating cell cycle, autophagy, and the ROS/p53/p21Cip1/Waf1 signaling pathway
27698927	Senescence Process in Primary Wilms' Tumor Cell Culture Induced by p53 Independent p21 Expression
27698927	There was also loss-of-expression of p53 in this cell line
27698927	In conclusion, cellular senescence was responsible for limited proliferation in the primary culture of WT, which was also associated with increased expression of p21 and was independent of p53 expression
27362652	Senescence markers including p16, p21, p53, and senescence-associated beta-galactosidase (SA-betagal) activity were measured in type II AECs from IPF lungs and unused donor lungs
27362652	Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs
27352265	The identification of p53 gene mutation has been studied at NIH, Washington, DC, USA, in urine samples of bladder cancer patients
27352265	The invasive bladder cancers were determined for the presence of gene mutations on p53 suppressor gene
27352265	The 18 different bladder tumors were evaluated, and 11 (61 %) had genetic mutations of p53 gene
27340387	Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells
27329245	Hormone ablation upregulated senescence-associated (SA)-beta-Gal activity in prostate glands, as well as the expressions of p27KIP1 and p53, in a mouse castration model
27324096	Tissues were examined for Telomere length (TL) and the presence of Phosphorylated (P) p38MAPK and p53, p21 and senescence associated beta-Galactosidase (SA- beta-Gal)
27324096	Activation of p53 was progressive in fetal membranes
27324096	In contrast, active p53 was constitutive in placenta and decidua/uterus throughout gestation
27294914	X), 8-OHdG, p16(Ink4a), Rb, p21(Cip1/Waf1) and p53 in senescent Sca-1(+) HSC/HPCs
27238838	The downstream events and target genes of p53 in the process of senescence are not fully understood
27238838	Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence
27229617	Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status
27229617	Induction of SIRT2 expression during senescence was dependent on p53 status as depletion of p53 by shRNA prevented its accumulation
27229617	Chromatin immunoprecipitation revealed the presence of p53 binding sites on the SIRT2 promoter suggesting its regulation by p53, which was also corroborated by the SEAP reporter assay
27229617	Overall, our results suggest SIRT2 as a promising marker of cellular senescence at least in cells with wild type p53 status
27229128	Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma
27229128	These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations
27229128	Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma
27229128	This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth
27212655	Senescent cells were identified based on declining population doublings, increased expression of senescence markers p16 and p53 and increased senescence-associated beta-gal activity
27212655	The oxidative stress-sensitive proteins ataxia-telangiectasia mutated and p53 were phosphorylated, and the expression of apoptosis molecules Bax increased, and Bcl-2 decreased in early passage MSCs; however, the expression of the apoptotic molecules did less change in response to apoptotic stimulation in late-passage MSCs, suggesting that the intrinsic apoptotic signalling pathway was not induced by oxidative stress in long-term-cultured MSCs
27208501	Shifting p53-induced senescence to cell death by TIS21(/BTG2/Pc3) gene through posttranslational modification of p53 protein
27208501	Cellular senescence and apoptosis can be regulated by p53 activity, although the underlying mechanism of the switch between the two events remains largely unknown
27208501	By employing adenoviral transduction of p53 or TIS21 genes, we observed shifting of p53 induced-senescence to apoptosis in EJ bladder cancer cells, which express H-RasV12 and mutant p53; transduction of p53 increased H-RasV12 expression along with senescence phenotypes, whereas coexpression with TIS21 (p53+TIS21) induced cell death rather than senescence
27208501	The TIS21-mediated switch of senescence to apoptosis was accompanied by nuclear translocation of p53 protein and its modifications on Ser-15 and Ser-46 phosphorylation and acetylations on Lys-120, -320, -373 and -382 residues
27208501	Mechanistically, TIS21(/BTG2) regulated posttranslational modification of p53 via enhancing miR34a and Bax expressions as opposed to inhibiting SIRT1 and Bcl2 expression
27208501	At the same time, TIS21 increased APAF-1 and p53AIP1 expressions, but inhibited the interaction of p53 with iASPP
27208501	Effect of TIS21 on the regulation of p53 activity was confirmed by knockdown of TIS21 expression by RNA interference
27208501	Therefore, we suggest TIS21 expression as an endogenous cell death inducer at the downstream of p53 gene, which might be useful for intractable cancer chemotherapy
27183917	Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity
27183917	Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression
27183917	To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D
27183917	When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation
27181777	Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage
27181777	In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence
27181777	Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53
27129219	We found that HBP1 activates the p21 gene through enhancing p53 stability by inhibiting Mdm2-mediated ubiquitination of p53, a well known positive regulator of p21
27126529	Inactivation of the premature senescence program by genetic ablation of p53 and p16(INK4a) (Trp53(-/-)Cdkn2a(-/-) mice) resulted in aggravated fibrosis after transverse aortic constriction, when compared with wild-type control subjects (49 +/- 4
27113195	In addition, we found that telomeres in Pot1b(/) ; p53(-/-) mice activate an ATR-Chk1-dependent DNA damage response to initiate a robust p53-independent, p73-dependent apoptotic pathway that limited stem cell proliferation but suppressed B-cell lymphomagenesis
27106773	To evaluate the expression of markers correlated with cellular senescence and DNA damage (8-hydroxy-2'-deoxy-guanosine (8-OHdG), p53, p21, APE1/Ref-1 (APE1), interleukin (IL-6 and IL-8) in placentas from healthy and pathologic pregnancies
27106773	In this study, we demonstrated a significant influence of gestational age on the expression in the trophoblast of 8-OHdG, p53, p21, APE1, and IL-6
27106773	In placentas of cases affected by PE, HELLP, or IUGR, there was an increased expression of 8-OHdG, p53, APE1, and IL-6 compared to controls (only IL-8 was significantly decreased in cases)
27106773	Moreover, p53 was increased after 34-week gestation in IUGR pregnancies
27106773	Placentas from pathological pregnancies had an altered expression of 8-OHdG, p53, p21, APE1, IL-6, and IL-8
27104929	We here demonstrate that the p53 isoforms Delta133p53 and p53beta are expressed in astrocytes and regulate their toxic and protective effects on neurons
27104929	Our finding that Delta133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases
27092462	Furthermore, stromal cells senescence was through p53 and p16 pathways
27077805	We further demonstrated that P53 pharmacological inhibitor pifithrin-alpha (PFT-alpha) or transfection with P53 siRNA abrogated the curcumin-induced HSC senescence in vitro
27077805	Meanwhile, curcumin disruption of P53 leading to increased senescence of activated HSCs was further verified in vivo
27077805	Further studies indicated that curcumin promoted the expression of P53 through a PPARgamma activation-dependent mechanism
27063514	DDR-induced signaling in cells activates the ATM-p53 and ATM-IKKalpha/beta-interferon (IFN)-beta signaling pathways, thus leading to an induction of the p53 and IFN-inducible IFI16 gene
27048913	Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14(ARF)
27048255	The expressions of caveolin-1 and P53 proteins were determined by Western blot
27048255	Results: Treatment with high concentrations of glucose induced GMC senescence accompanied by shortened telomere length and increase of beta-galactosidase staining as well as P53 protein, which was abrogated after application of caveolin-1-siRNA
27048255	The effect of caveolin-1 is mediated by P53 pathway
27041461	Activation of p53 contributes to pseudolaric acid B-induced senescence in human lung cancer cells in vitro
27041461	The expression of p53 and p21 in the cells was downregulated by siRNAs
27041461	Knockdown of p53 expression with siRNA significantly suppressed PAB-induced senescence in A549 cells (p53 wild)
27041461	Furthermore, PAB-induced senescence was also observed in human lung cancer H460 cells (p53 wild), but not in human lung cancer H1299 cells (p53 null)
27041461	CONCLUSION: The anti-tumor action of PAB against human lung cancer A549 cells in vitro involves the induction of senescence through activation of the p53 pathway
27039820	The fact that bromodeoxyuridine had the strongest effects on growth inhibition and senescence induction implies that senescence in cholangiocarcinoma cells is likely controlled by DNA damage response pathways relating to the p53/p21 signaling
27036204	Senescence biomarkers, including p53, p21, and p16, were upregulated in P6 cells relative to P3 cells
26997276	Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation
26997276	Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH
26997276	Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence
26941359	Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated beta-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression
26940203	SIRT1 alleviates senescence of degenerative human intervertebral disc cartilage endo-plate cells via the p53/p21 pathway
26940203	In addition, the results indicated that p53/p21 pathway plays an important role in the senescence of CEP cells in vivo and vitro
26940203	Furthermore, SIRT1 was found to be capable of alleviating the oxidative stress-induced senescence of CEP cells in humans via p53/p21 pathway
26934949	Moreover, Apr3 overexpression promoted cellular senescence in ARPE19 cells, as characterized by enhanced senescenceassociated betagalactosidase activity, reduced cell proliferation and increased expression of the senescence markers p53 and p21
26924930	Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling
26924930	Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine
26924930	Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21
26915821	Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation
26915821	Poly(C)-binding protein 4 (PCBP4), also called MCG10 and a target of p53, plays a role in the cell cycle and is implicated in lung tumor suppression
26915821	We also found that p53 expression is markedly reduced in PCBP4-deficient MEFs and mouse tissues, suggesting that PCBP4 in turn regulates p53 expression
26915821	To determine how PCBP4 regulates p53 expression, PCBP4 targets were identified by RNA immunoprecipitation followed by RNA sequencing (RNA-seq)
26915821	Additionally, we found that ZFP871 physically interacts with p53 and MDM2 proteins
26915821	Moreover, loss of ZFP871 reverses the reduction of p53 expression by lack of PCBP4, and thus increased expression of ZFP871 is responsible for decreased expression of p53 in the PCBP4-deficient MEFs and mouse tissues
26915821	Interestingly, we found that, like PCBP4, ZFP871 is also regulated by DNA damage and p53
26915821	Finally, we showed that knockdown of ZFP871 markedly enhances p53 expression, leading to growth suppression and apoptosis in a p53-dependent manner
26915821	Thus, the p53-PCBP4-ZFP871 axis represents a novel feedback loop in the p53 pathway
26915821	Together, we hypothesize that PCBP4 is a potential tissue-specific tumor suppressor and that ZFP871 is part of MDM2 and possibly other ubiquitin E3 ligases that target p53 for degradation
26904954	During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown
26904954	We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb) tumor suppressor pathways
26868148	SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence
26868148	Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established
26868148	We demonstrate here that SCF(Fbxo22)-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation
26868148	We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCF(Fbxo22) ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A
26868148	Ectopic expression of a catalytic mutant of KDM4A stabilizes p53 and enhances p53 interaction with PHF20 in the presence of Fbxo22
26868148	Fbxo22(-/-) mice are almost half the size of Fbxo22(+/-) mice owing to the accumulation of p53
26866709	Senescence is considered a tightly regulated stress response that is largely governed by the p53/p21 and p16/Rb pathways
26833729	We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging
26833729	We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients
26823782	However, some important signal pathways including MAPK, the insulin signaling pathway, pathways involved in carcinogenesis such as PPAR and P53, and cytokines and their receptors, as well as other pathways associated with immune response and aging, changed to various extents under the conditions of aging after a long time in vitro
26820992	Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice
26820992	Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities
26797283	The FGF-23-treated MSCs exhibited the senescent phenotype, as judged by senescence-associated beta-galactosidase assay, cell morphology, and increased expression of p53 and p21 in western blot analysis
26797283	In conclusion, FGF-23 induced premature senescence in MSCs from skeletal muscle via the p53/p21/oxidative-stress pathway
26792455	The tumor suppressor protein p53 is an important player in the regulation of cell senescence, its functions are largely carried out by modulating its downstream genes
26792455	In this study, we sought to explore the effects of the expression pattern and function of p53 on the activity of autophagy and replicative senescence in bone marrow derived mesenchymal stromal cells (BMSCs)
26792455	These results were accompanied by the up-regulation of p53, down-regulation of mammalian target of rapamycin (mTOR) and phosphorylation of Rb
26792455	Knockdown of p53 alleviated the senescent state and reduced autophagic activity during the progression of BMSC senescence, which was accompanied by significantly up-regulated levels of mTOR and phosphorylation of Rb
26792455	These results demonstrate that autophagy increases when BMSCs enter the replicative senescence state, and p53 contributes a crucial role in the up-regulation of autophagy in this state
26763147	Expression of hCMV immediate early (IE) and early (E) proteins and senescence-associated proteins (pRb and Rb, p16(INK4), and p53) and production of reactive oxygen species (ROS) were assessed using standard laboratory assays
26721440	Examination of the causal relationship between pNO40 deficiency and MSC-accelerated aging revealed big up tri, openE4 null disruption in MSCs elicits high levels of ROS and elevated expression levels of p16 and Rb but not p53
26696133	In addition, the levels of some senescence-associated proteins, such as phosphorylated ERK1/2, caveolin-1, p53, p16(ink4a), and p21(waf1), were elevated in PPKO-treated cells
26686024	Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation
26677981	In addition, miR-34a overexpression decreased the expression of various cell cycle regulators such as CDKs (-2, -4, -6) and cyclins (-E, -D), but not p21 and p53
26677227	We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor
26677227	These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence
26676339	Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter
26676339	Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear
26676339	To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells
26676339	Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2)
26676339	We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide
26676339	Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription
26676339	These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression
26675707	We confirmed that mESC-CM treatment accelerates the wound-healing process by down-regulating senescence-associated p53 expression in in vivo models
26640145	In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence
26640145	Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis
26640145	The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis
26640145	Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53
26640145	Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status
26636375	Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition
26636375	Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated
26636375	In the present study by using the specific inhibitors Ku55933 and Pifithrin-alpha, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs
26636375	ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs
26636375	ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells
26636375	On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction
26636375	The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy
26635065	Conclusion EBV radiosensitized the p53 mutant tobacco associated head and neck cell line, FaDu
26635065	This study aimed to evaluate whether viral infections can sensitize tobacco-associated head and neck squamous cell carcinoma cell line that harbors multiple mutations, especially TP53, to radiotherapy
26629991	It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent "memory
26629991	Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of "metabolic memory
26629698	Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus
26598601	The restoration of p53 has been suggested as a therapeutic approach in tumors
26598601	However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear
26598601	We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not
26598601	The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression
26598601	In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction
26598601	Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression
26598601	The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway
26598601	Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again
26598601	Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors
26589970	Whereas the increased p16 expression and SAHF were concomitant with that of beta-galactosidase, those of p53 and p21 were barely detected
26583757	Furthermore, inhibition of the p53 or Rb pathway failed to prevent the SASP-inducing effect of pro-senescence kinases
26583757	Inhibition of the NF-kappaB, p53, or Rb pathway proved insufficient to prevent kinase-triggered cell cycle arrest
26583057	We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex
26573462	The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs
26511486	We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-beta-galactosidase staining, and reduced Ki67 cell proliferation index in Pten KO prostate epithelium
26511486	Because p53 signaling is likely to be intact in HG-PIN compared with advanced prostate cancer, the selective superactivation of p53-mediated senescence by MSeA suggests a new paradigm of cancer chemoprevention by strengthening a cancer progression barrier through induction of irreversible senescence with additional suppression of AR and AKT oncogenic signaling
26503169	The senescence levels of Numb-deficient muscle is reduced to wild type levels by an anti-oxidant treatment or p53 ablation, resulting in functional rescue of the regenerative potential in Numb mutants
26503169	These findings provide insights into previously reported developmental and oncogenic senescence that are also differentially regulated by p53
26494712	A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence
26477465	Although cancer cells frequently possess mutations in two main signalling pathways involved in cell senescence, namely p53/p21 and p16/Rb, they still preserve the ability to undergo DNA damage-induced senescence
26476632	In the aorta, RBEE treatment reduced expression of the apoptosis pathway components p16, p53 and bax/bcl-2 ratio
26476632	In contrast, MNC of RBEE-fed mice exhibited enhanced apoptosis marker expression with increased p53 and bax/bcl-2 protein levels
26474698	The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3beta) activity and phosphorylated beta-catenin (p-beta-catenin) level as well as an increase in beta-catenin and p53 levels within the endothelium
26474698	Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3beta activity and p-beta-catenin level as well as an increase in HOCl content, beta-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor
26472020	Most ROSmiRs' expression and function were influenced and regulated by p53, and together they drove the cells into stress-induced premature senescence (SIPS)
26472020	However, ROS-induced miR-182 is regulated by beta-catenin, not by p53
26472020	These findings suggest that ROS and p53 mutations may trigger a series of events, beginning with overexpressing miR-182 by ROS and beta-catenin, impairing the DNA damage response, promoting DNA instability, bypassing senescence and eventually leading to DNA instable tumors in FTSE cells
26469953	The mechanism involves not only the inhibition of autophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization of both the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1
26467393	Seven/eight nephrectomized rats feeding a hyperphosphatemic diet and fifteenth- month old mice showed hyperphosphatemia and aortic ILK, p53 and p16 expression
26465338	These phenotypic changes were not accompanied by colonies forming in soft agar and a continuous decrease in the senescence-associated proteins p53 and pRB which act as a barrier to tumorigenesis
26461417	In support, partial inhibition of proteasomes in young cells by specific inhibitors induces premature senescence which is p53 dependent (Aging Cell 7, 717-732, 2008)
26461417	Finally, we have studied the proteolysis processes of various age-related proteins and we have identified that CHIP is a major p53 E3 ligase in senescent fibroblasts (Free Rad Biol Med 50, 157-165, 2011)
26448623	Furthermore, IGF-I-treated cells showed increased senescence-associated beta-galactosidase activity and expression of p53 and p21 protein
26439691	The ING1a epigenetic regulator synchronously induces senescence in mass cultures several-fold faster than all other agents, taking 24 and 36 hours to activate the Rb/ p16INK4a, but not the p53 tumor suppressor axis to efficiently induce senescence
26439195	Collectively, we showed that overexpression of AP4 mediates cellular senescence involving in activation of p53 in long-term post-confluent RPE cells
26437300	Decreased protein levels of the shelterin subunits, shortened telomere length, over-expressed Ki-67, and Bcl2 as well as mutations in P53 were detected both in MGC and BCC
26437300	However, several parameters distinguish MGC from BCC samples: (i) the mRNA level of the shelterin subunits decreased in MGC but it increased in BCC; (ii) P53 was more highly mutated in MGC; (iii) Siah1 mRNA was over-expressed in BCC; (iv) BCC samples contain a higher level of senescent cells; (v) Ki-67 and Bcl2 expression were lower in BCC
26437300	These results support a model where a preserved P53 checkpoint in BCC leads to cellular senescence and reduced tumor proliferation as compared to MGC
26412380	We have found evidence suggesting that ARF and p53 are essential for tumor regression upon MYC inactivation through distinct mechanisms ARF through p53-independent affect, is required to for MYC to regulate the expression of genes that are required for both the induction of cellular senescence as well as recruitment of innate immune activation
26408226	In PC12 cells, treatment with glutamate induced senescent phenotypes as judged by the cell appearance and senescence-associated ss-galactosidase (SA-ssgal) in parallel with decreased SIRT1 and increased p53 expression
26408226	However, treatment with memantine decreased glutamate-induced senescent PC12 cells and reversed the changes in SIRT1 and p53 expression
26404840	Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins
26404840	GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a)
26392399	Telomere attrition activates downstream p53 signaling and compromises mitochondrial metabolism via the peroxisome proliferator-activated receptor gamma co-activator 1alpha/beta (PGC-1alpha/beta), a key process possesses peculiarities in BMMSCs distinct from other stem cells and their mature derivatives
26381291	Mechanistically, DUSP16 silencing causes cellular senescence by activating the tumor suppressors p53 and Rb
26345860	Based on the established cell replicative senescence model, reverse transcription-polymerase chain reaction and western blot analyses were used to detect telomere-associated factor expression at the mRNA and protein levels, including that of human telomere binding protein 1, tankyrase 1, telomerase RNA, telomere protection protein 1 (POT1), and p53 during the process of human embryonic lung fibroblast replicative senescence
26345860	The results showed that transcription of human telomere binding protein 1 did not change with cell senescence, whereas the protein expression of human telomere binding protein 1 increased gradually and then decreased rapidly; there was no change in the mRNA and protein expression of POT1; with the replicative senescence of human embryonic lung fibroblasts, expression of POT1 decreased gradually; TRF1 showed an increasing trend with cell senescence; and p53 protein expression did not change
26331977	We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence-associated secretory phenotype (SASP) and other senescence-associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence
26330291	We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+)
26309394	20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway
26309394	Moreover, induction of cellular senescence and G0/G1 arrest by 20(S)-Rg3 were accompanied by a large accumulation of p53 and p21 as a result of murine double minute 2 (MDM2) inhibition
26309394	20(S)-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis
26299964	PGC-1alpha deletion reduces expression and activity of telomerase reverse transcriptase (TERT) and increases p53 levels
26292757	Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors
26287165	In addition, p53 phosphorylation and p21 expression were significantly reduced in senescent fibroblasts treated with hDSPC-CM
26250908	Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis
26246868	Moreover cells obtained from older patients displayed senescence associated features, for example, beta-galactosidase activity, enlarged morphology, and p53 protein upregulation
26240351	Concomitantly, increased cellular senescence in the adipose tissue from pol eta(-/-) mice was observed and measured by up-regulation of senescence markers, including p53, p16(Ink4a), p21, senescence-associated (SA) beta-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) as early as 4 wk of age
26240351	Treatment of pol eta(-/-) mice with a p53 inhibitor, pifithrin-alpha, reduced adipocyte senescence and attenuated the metabolic abnormalities
26236688	The differential molecular profiles between MOE(HIGH) and MOE(LOW) were determined using RNA-Seq and confirmed by protein expression to uncover pathways important in transformation, like the p53 pathway, the FOXM1 pathway, WNT signaling, and splicing
26236688	MOE(HIGH) had enhanced protein expression of c-myc, Cyclin E, p53, and FOXM1 with reduced expression of p21
26224580	On a negative side, statins impaired the osteogenic and chondrogenic differentiation potential of MSCs and increased cell senescence and apoptosis, as indicated by upregulation of p16, p53 and Caspase 3, 8, and 9
26215037	Western blot was used to assess SHP-1, p21, p53, pRb, Rb, H3K9Me3, HP1gamma, CDK4, cyclin D1, cyclin E, and p16 protein expressions
26215037	Levels of p53 and p21 were unchanged in both cell lines (all P > 0
26206128	In order to categorize chemicals, we used p53 gene-modified mouse ES cells as well as wild-type ES cells
26206128	The p53 gene is a well-known tumor suppressor and controls programmed cell death (apoptosis) and cellular senescence that is triggered by DNA-damaging agents such as alkylating agents and radiation
26206128	In the present study, p53-deficient ES cells were found to be more resistant to a tumor initiator, diethylnitrosamine (DEN), than wild-type ES cells, suggesting the inhibition of apoptosis or senescence by a dysfunction in p53
26206128	Chromosome aberrations were more frequently detected in p53-deficient ES cells than in wild-type cells, indicating genomic instability due to the deletion of p53
26181202	Targeting Mdmx to treat breast cancers with wild-type p53
26181202	The function of the tumor suppressor p53 is universally compromised in cancers
26181202	In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions
26181202	This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed)
26181202	In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53
26181202	Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status
26181202	The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53
26181202	These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes
26181202	Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53
26169984	Novel protein-protein interactions of TPPII, p53, and SIRT7
26169984	Novel protein-protein interactions of TPPII, SIRT7, and p53 were detected by co-immunoprecipitation using both HeLa cell lysates and the cytoplasmic fraction prepared by fractionation of mouse liver tissue
26169984	The interactions of SIRT7 with p53 were confirmed in three HEK293 cell transformants as well
26169984	The cytoplasmic localization of p53 detected by immunofluorescence supported the results from its interactions with TPPII and SIRT7 observed by in situ PLA within model cells
26169984	Novel interactions of TPPII, p53, and SIRT7 presented in this study might contribute to the knowledge of the regulatory effects of these proteins on apoptotic pathways and to the understanding mechanisms of aging and lifespan regulation
26159917	Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1
26152738	When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status
26106036	Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction
26105007	In addition, LPS induced features of premature senescence of SV cells, including the activation of p53, the elevation of SA-beta-gal activity, and increased hydrogen peroxide production, but not telomere length
26096152	Knockdown of p21 restored iPSC generation even in long-term passaged fibroblasts of an old donor, highlighting the central role of the p53/p21 pathway in cellular senescence induced by both donor age and culture time
26078718	NQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence
26078718	Analysis of the mechanism underlying the up-regulation of NQO1 expression during senescence identified that NQO1 promotes p53 accumulation in an MDM2 and ubiquitin independent manner, which reinforces the cellular senescence phenotype
26029982	Mutant lamin A links prophase to a p53 independent senescence program
26029982	Expression of oncogenes or short telomeres can trigger an anticancer response known as cellular senescence activating the p53 and RB tumor suppressor pathways
26029982	This mechanism is switched off in most tumor cells by mutations in p53 and RB signaling pathways
26029982	Surprisingly, p53 disabled tumor cells could be forced into senescence by expression of a mutant allele of the nuclear envelope protein lamin A
26020242	Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling
26020242	Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model
26020242	Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence
26008970	However, down-regulation of the enzyme-induced cellular senescence was not through p53
26004298	In previous work, we reported that EZH2 depletion functionally induced cellular senescence in human gastric cancer cells with mutant p53
25994420	Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells
25993799	Expression of aging-related p53, p21, p16, Rb mRNA and P16, Rb, CDK4 and Cyclin E protein were detected by quantitative reverse transcription polymerase chain reaction( qRT-PCR) and Western blotting, respectively
25993799	Aging-related p53, p21, p16, Rb and P16, Rb were up-regulated, protein regulatory cell-cycle CDK4 and Cyclin E were down-regulated
25989537	METHODS: Cellular senescence was measured by staining of senescence-associated beta-galactosidase and by expression of the cell cycle inhibitors p53 and p21
25967604	Furthermore ASMq up-regulated the tumor suppressor genes p21, p53 and p16 and down-regulated the micro-RNAs hsa-mir-17 and hsa-mir-106b
25964555	MATERIALS AND METHODS: Multiplex Ligation-dependent Probe Amplification, TP53 sequencing, real-time polymerase chain reaction (PCR) for MUC1 and SCGB2A2 and immunocytochemistry, together with senescence detection assay and real-time microscopic observations were used to analyze primary neoplastic cells isolated from prostate, breast and colorectal tumors, as well as stable cancer cell lines (MCF7, MDA-MB-468, SW962, SK-MEL28, NCI-H1975 and NCI-H469)
25958121	Moreover, treatment of ascorbic acid inhibited p53 accumulation at 3 days after irradiation
25958121	Our data suggested a delayed increase of intracellular oxidative stress levels plays an important role in the process of radiation-induced cellular senescence by p53 accumulation
25952632	Under these conditions, the anti-senescence genes TERT, bFGF, VEGF, and ANG were increased, whereas the senescence-related genes ATM, p21, and p53 were decreased
25937285	These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation
25924011	A significant increase in phosphorylation of gamma-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected
25924011	Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-beta-gal activity, gamma-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels
25882843	Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated beta-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs
25879755	Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
25879755	Deletion of p53 rescued the multilineage repopulation defect of Wip1(-/-) HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways
25879755	However, p53 deletion did not influence the increased HSC pool size in Wip1(-/-) mice
25879755	Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1
25869441	Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised
25855056	These effects correlated with CR-mediated increases in SIRT1 and decreases in p53 expression levels
25852816	Cell senescence was found to appear prematurely in DS cells as shown by SA-beta-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F
25844948	Irradiated (2, 4, 6 and 8 Gy) human colorectal carcinoma cells (HCT116) with p53(+/+) (wild-type) or p53(-/-) (knockout) gene were co-incubated with nonirradiated cells of the same type
25844948	61% for p53(+/+) vs
25844948	19% for p53(-/-) in irradiated population; 3
25839657	Intracellular ROS levels were increased in hBM-MSCs; this was accompanied by a decrease in the expression of the antioxidant enzymes catalase and superoxide dismutase (SOD)1 and 2 and of phosphorylated forkhead box O1 (p-FOXO1) as well as an increase in the expression of p53 and p16, along with a reduction in differentiation potential
25839657	When the antioxidant ascorbic acid was used to eliminate excess ROS, the levels of antioxidant enzymes (catalase, SOD1 and 2, p-FOXO1, and p53) were partly restored
25815425	Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of 'DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)'
25792665	Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin
25784651	Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression
25784651	Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications
25784651	Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment
25766317	One potential biomarker to determine radioresistance is TP53 whose alterations are predictive of poor radiation response
25766317	DNA-damaging reactive oxygen species (ROS) are a by-product of ionizing radiation that lead to the activation of p53, transcription of p21(cip1/waf1) and, in the case of wild-type TP53 HNSCC cells, cause senescence
25766317	For the first time, we show that persistent exposure to low levels of the ROS, hydrogen peroxide, leads to the long-term expression of p21 in HNSCC cells with a partially functional TP53, resulting in senescence
25766317	Our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation as approaches in cancer therapy and emphasizes the importance of considering TP53 status when selecting a patient's treatment options
25758253	The induction of apoptosis in response to alisertib exposure was dependent on p53 and p73 activity
25758253	In the absence of functional p53 or p73, there was a shift in the phenotypic response following alisertib exposure from apoptosis to cellular senescence
25758253	The role of p53 and p73 in mediating the phenotypic response to antimitotic agents in TNBC may be harnessed to develop an effective biomarker selection strategy in this difficult to target disease
25737737	Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression
25737737	Treatment of cells with pifithrin-alpha, a specific inhibitor of p53, suppressed shikonin-induced apoptosis and premature senescence, suggesting the role of p53 in mediating the actions of shikonin on regulation of lung cancer cell proliferation
25732822	Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation
25732822	The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress
25732822	Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress
25732822	Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence
25732822	We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan
25716429	Among them, compound 4 (quercetagetin 3,4'-dimethyl ether) showed inhibitory activity against cellular senescence, which was confirmed by senescence-associated beta-galactosidase (SA-beta-gal) activity, p53 and p21 protein levels, and intracellular ROS levels
25703056	In addition, we observed counteraction of cell-cycle arrest and repression of UVB-induced p53 and p21 in the presence of RO
25698579	The inhibitory role of p53 in DNA double-strand break (DSB) repair seems contradictory to its tumor-suppressing property
25698579	The p53 isoform Delta113p53/Delta133p53 is a p53 target gene that antagonizes p53 apoptotic activity
25695870	Although much is known about the key players in the implementation of senescence, including the pRb and p53 axes and the cyclin dependent kinase inhibitors p16(INK4a) and p21(CIP1), many details remain unresolved
25695870	At the permissive temperature, where pRb and p53 are functionally compromised by T-Ag, cyclin D-CDK4 complexes are disrupted by the high p16(INK4a) levels and reduced expression of p21(CIP1)
25655936	Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults
25622904	Sag inactivation by genetic deletion remarkably suppresses cell proliferation by inducing senescence, which is associated with accumulation of p16, but not p53
25607652	KSHV latent protein LANA2 inhibits sumo2 modification of p53
25607652	Tumor suppressor p53 plays a crucial antiviral role and targeting of p53 by viral proteins is a common mechanism involved in virus oncogenesis
25607652	The activity of p53 is tightly regulated at the post-translational levels through a myriad of modifications
25607652	Among them, modification of p53 by SUMO has been associated with the onset of cellular senescence
25607652	Kaposi s sarcoma-associated herpesvirus (KSHV) expresses several proteins targeting p53, including the latent protein LANA2 that regulates polyubiquitylation and phosphorylation of p53
25607652	Here we show that LANA2 also inhibits the modification of p53 by SUMO2
25607652	These results highlight the importance of p53 SUMOylation in the control of virus infection and suggest that viral oncoproteins could contribute to viral infection and cell transformation by abrogating p53 SUMOylation
25593054	AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16
25593054	CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53
25565635	Molecular analysis of individual p53 transcripts did not reveal tumorigenic mutations
25565110	The bone sparing effects of SPI were associated with prevention of HF-Cas-induced osteoblast senescence pathways through suppression of p53/p21 signaling pathways
25565110	HF-Cas-fed rats had increased caveolin-1 and down-regulated Sirt1 leading to activations of PPARgamma and p53/p21; whereas, rats fed HF-SPI suppressed caveolin-1and activated Sirt1 to de-acetylate PPARgamma and p53 in bone
25560618	UVB-induced increases in the levels of p53 and p21, biomarkers of cellular senescence, were almost completely abolished in the presence of EEDO
25531190	We found that ATF3 regulated p53 and p21 levels
25512378	Reactive oxygen species stimulation promotes acetylation of p53 and premature senescence in wild-type but not caveolin-1 null mouse embryonic fibroblasts (MEFs)
25512378	Either down-regulation of Sirt1 expression or re-expression of caveolin-1 in caveolin-1 null MEFs restores reactive oxygen species-induced acetylation of p53 and premature senescence
25512378	In addition, overexpression of caveolin-1 induces stress induced premature senescence in p53 wild-type but not p53 knockout MEFs
25512378	Phosphorylation of caveolin-1 on tyrosine 14 promotes the sequestration of Sirt1 into caveolar membranes and activates p53/senescence signaling
25512378	Therefore, by inhibiting Sirt1, caveolin-1 links free radicals to the activation of the p53/senescence pathway and the protumorigenic properties of IL-6
25512341	Notably, lincRNA-p21 is induced by p53 but does not promote apoptosis or cell senescence in reprogramming
25512341	Our results provide insight into the role of lncRNAs in reprogramming and establish a novel link between p53 and heterochromatin regulation
25490147	The bone-sparing effects of SPI were associated with prevention of HF-Cas-induced osteoblast senescence pathways through suppression of the p53/p21 signaling pathways
25490147	HF-Cas-fed rats had increased caveolin-1 and down-regulated Sirt1, leading to activations of peroxisome proliferator-activated receptor gamma (PPARgamma) and p53/p21, whereas rats fed HF-SPI suppressed caveolin-1 and activated Sirt1 to deacetylate PPARgamma and p53 in bone
25482089	Compared with normal pituitary cells, the aging pituitary tissues revealed increased expression of IL6, C/EBPbeta, p53, p21 and p16 and decreased expression of pituitary tumor transforming gene
25482089	Taken together, multiple pathways including IL6/C/EBPbeta, p53/p21 and p16 were activated in aging pituitary cells in response to Dgal treatment
25464270	Tumor suppressor p53 is known to regulate the level of intracellular reactive oxygen species (ROS)
25464270	Ectopic expression of CUL4B, on the other hand, blunted p53 activation, reduced ROS production, and attenuated cellular senescence in cells treated with H2O2
25464270	CUL4B was shown to promote p53 ubiquitination and proteosomal degradation in NHFs exposed to oxidative stress, thus dampening the p53-dependent cellular senescence
25461770	A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate
25461770	This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a
25440825	Autophagy was evaluated by image analysis techniques for the expression of light chain 3 (LC3) after immunohistochemical staining of LC3 rabbit polyclonal antibody and Western blot analysis; additionally, myocyte apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, 4',6-diamidino-2-phenylindole staining, and p53 immunohistochemical staining
25437179	When compared with N-UC-MSCs, GDM-UC-MSCs showed decreased cell growth and earlier cellular senescence with accumulation of p16 and p53, even though they expressed similar levels of CD105, CD90, and CD73 MSC marker proteins
25437011	Activation of the Wnt pathway by treatment with Wnt3a-conditioned medium or glycogen synthase kinase 3beta inhibitors, such as SB-216763 and 6-bromoindirubin-3'-oxime, delays the progression of cellular senescence as shown by the decrease in the senescence effectors p53 and pRb, lowered senescence-associated beta-galactosidase activity, and increased telomerase activity
25416819	Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells
25414256	Exposure of normal rat epithelial cells to etoposide caused cellular senescence, as manifested by enlarged cell size, a flattened cell body, reduced cell proliferation, enhanced beta-galactosidase activity, and elevated p53 and p21
25414256	Further analysis revealed that senescent cells expressed a significantly higher level of mitogen-activated protein phosphatase 3 (MKP-3, a cytosolic ERK1/2-targeted phosphatase), which was suppressed by blocking the transcriptional activity of the tumor suppressor p53 with pifithrin-alpha
25407160	In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide
25398437	Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53
25382750	UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop
25382750	The tumour suppressor p53 plays an important role in tumourigenesis
25382750	The mechanism of regulation of cellular senescence by p53 and its downstream pathway are poorly understood
25382750	Here, we report that the ubiquitin domain-containing 1 (UBTD1) gene, a new downstream target of p53, induces cellular senescence and acts as a novel tumour suppressor by a mechanism that depends on p53
25382750	Furthermore, UBTD1 increased the stability of p53 protein, by promoting the degradation of Mdm2 protein
25382750	Importantly, UBTD1 and p53 function mutually depend on each other in regulating cellular senescence and proliferation
25382750	Thus, our data suggest that, upon DNA damage, p53 induction by UBTD1 creates a positive feedback mechanism to further increase p53 expression
25382750	Our results establish UBTD1 as a regulator of cellular senescence that mediates p53 function, and provide insights into the mechanism of Mdm2 inhibition that impacts p53 dynamics during cellular senescence and tumourigenesis
25378661	In addition, knockdown of EPAC2 or CALR increased senescence-associated beta galactosidase activity and expression of p21 but decreased expression of p53
25369834	The tumor suppressor p53 is widely known for its ability to induce cell cycle arrest or cell death, therefore preventing neoplastic progression
25369834	Previous studies have demonstrated novel roles for p53 in the regulation of autophagy and senescence
25369834	The present study demonstrated that p53 was capable of activating autophagy, which permits cell survival under conditions of serum starvation, and suppresses cellular senescence through inhibition of the mammalian target of rapamycin pathway
25369834	The findings of the present study provide a potential mechanism for suppression of senescence by p53
25367309	In this study, we found that ACLY knockdown in primary human cells triggers cellular senescence and activation of tumor suppressor p53
25367309	Provision of acetyl CoA to ACLY knockdown cells did not alleviate ACLY silencing-induced p53 activation, suggesting an independent role for ACLY activity
25367309	In cancer cells, ACLY silencing-induced p53 activation facilitated DNA damage-induced cell death
25363496	Western blot assay was compared for p53, bax, cleaved caspase 3, rH2AX, and APE1
25363496	All the checked variables were significantly increased with aging: 1) increased p53, bax, and caspase 3 may activate the apoptotic pathway, 2) increased rH2AX and 8-OHdG immunolocalization in the proximal convoluted tubules might mean augmented DNA damage, and 3) increased APE1 might be caused by the immunoreactivity in the distal convoluted tubules while decreased in the proximal convoluted tubules
25359865	APPROACH AND RESULTS: When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages
25351164	This was accompanied with augmented expression of the cell cycle inhibitor p53
25345622	5, the trophoblast cells in the labyrinth layer of the placentas also showed strong activities of SA-beta-gal, p53 and p21
25345385	Mechanistically, mitochondrial defects in conjunction with Ras cause production of reactive oxygen species, downregulation of CycE activity and activation of p53, which cooperate together to trigger a cell cycle arrest-Jun N-terminal kinase (JNK) feedback loop that amplifies JNK activation, leading to upregulation of the inflammatory cytokine Unpaired
25338966	A novel pyrido-thieno-pyrimidine derivative activates p53 through induction of phosphorylation and acetylation in colorectal cancer cells
25338966	The tumor suppressor p53 plays a key role in regulation of the cell cycle, apoptosis and senescence in response to various stresses
25336634	Oxidative stress and persistent DNA damage response contribute to cellular senescence, a degeneration process critically involving ataxia telangiectasia-mutated (ATM) and p53
25336634	Such senescence phenotypes were alleviated in the presence of ATM kinase inhibitors, by p53 shRNA knockdown, or by maintaining the cells under 3% O2
25336634	Altogether, SelH protects against cellular senescence to oxidative stress through a genome maintenance pathway involving ATM and p53
25293814	X-ray and ultraviolet C irradiation-induced gamma-H2AX and p53 formation in normal human periosteal cells in vitro: markers for quality control in cell therapy
25293814	To develop a more efficient, inclusive and sensitive methodology, we examined the phosphorylation of histone H2AX and the p53 levels in normal human periosteal cells exposed to x-rays or other oxidative stressors
25293814	The cell cycle, electric nuclear volume and CD44 expression were evaluated using flow cytometry, and the phosphorylated H2AX (gamma-H2AX), p53, p21 and proliferating cell nuclear antigen (PCNA) levels were evaluated by Western blot analyses
25293814	In parallel, each oxidative stress rapidly phosphorylated H2AX and stabilized p53, and intense stress sustained these high levels for at least 8 days
25293814	CONCLUSIONS: Intensive oxidative stress induces sustained high levels of gamma-H2AX and p53, which force cells toward senescence or non-apoptotic cell death
25293814	Lower doses of oxidative stress induced more modest and transient increases in gamma-H2AX and p53, and these cells eventually survive
25293814	Therefore, we recommend that any cell population expressing elevated gamma-H2AX and p53 levels be excluded from cell transplantation therapy
25273595	JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner
25273595	The latter effect appears to be mediated by a p38-dependent phosphorylation of p53, inducing the expression of p15(Ink4b) and p21(Waf1)
25273595	In addition, in tumors lacking the controller function of p53, a lower expression of JHDM1B is associated with an increased tumor size at diagnosis
25273595	Altogether, our data indicate that epigenetic activation of rDNA genes induced by JHDM1B depletion is associated with a p53-dependent growth arrest, but may promote cancer cell growth when p53 is lacking
25255445	Regulation of p53 and Rb links the alternative NF-kappaB pathway to EZH2 expression and cell senescence
25255445	Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-kappaB2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53
25255445	Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1
25255445	We show that this pathway provides the major route of crosstalk between the alternative NF-kappaB pathway and p53, a consequence of which is to suppress cell senescence
25189993	Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target
25173500	PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3
25165029	Molecular Insights into SIRT1 Protection Against UVB-Induced Skin Fibroblast Senescence by Suppression of Oxidative Stress and p53 Acetylation
25165029	In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB
25149358	Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB
25149358	Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53
25149358	In conclusion, for both oncogene- and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence
25142166	Among the analyzed apoptosis-associated proteins, p21 was down-regulated and phosphorylated p53 was up-regulated
25142166	These results suggested that induced growth suppression or cell senescence was induced by strong heat stress rather than mild one predominantly in cells bearing long telomeres with p53 activation, and simultaneously activated some telomere-associated factors, heat shock proteins, and NO synthesis probably for heat-resistant cell survival
25134360	The key protein in the DDR pathway is p53
25134360	In cell senescence the p53 protein leads to the induction of p21, which causes cell cycle arrest
25134360	In apoptosis p53 participates in the activation of caspases, which are responsible for the degradation of many proteins
25132913	No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53
25118260	Senescence-associated beta-galactosidase (SA-beta-gal) activity was detected by histochemistry, and p53 expression by immunoblotting
25093836	We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate
25078983	The protein levels of telomerase reverse transcriptase (TERT), UCP2, Akt, phosphor (p)-Akt, c-myc, and p53 were assessed by immunoblot
25078983	LY294002 pre-treatment significantly alleviated Ang II-induced HUVEC senescence, and partly reversed the elevation of TERT, UCP2, p-Akt, c-myc and p53 protein levels
25070626	While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner
25070626	We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence
25070626	In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence
25070626	Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging
25064843	Knockdown of PLD2 dramatically induced senescent phenotype in proliferating IMR-90 cells and wild-type HCT116 colon cancer cells, whereas this response was nearly abolished in p53- or p21(Cip1/WAF1)-null HCT116 cells
25043688	We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry
25043688	Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex
25043688	An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol
25043688	After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated beta-galactosidase activity
25042573	Specifically, we address how p53 and telomerase reverse transcriptase (TERT) activity switch their roles from cytoprotective to detrimental and also examine the role of microRNAs in cell aging
24979747	Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1beta, IL-6 and TNF-alpha, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats
24979267	Dicer cooperates with p53 to suppress DNA damage and skin carcinogenesis in mice
24979267	We have previously examined the role of miRNA biogenesis in mouse embryonic fibroblasts and found that deletion of Dicer induces cell senescence regulated, in part, by the p53 tumor suppressor
24979267	Co-ablation of Dicer and p53 did not alter the timing or extent of fur loss, but greatly reduced survival of Dicer-skin ablated mice, as these mice developed multiple and highly aggressive skin carcinomas
24979267	Furthermore, our findings reveal that loss of Dicer in the epidermis induces extensive DNA damage, activation of the DNA damage response and p53-dependent apoptosis, and that Dicer and p53 cooperate to suppress mammalian skin carcinogenesis
24934763	We further noted that expression of p53 blocks the neuronal conversion, whereas expression of human telomerase reverse transcriptase (hTERT) induces it
24925089	JMJD3 can also enhance the nuclear localization of p53 and thus regulate its function
24925089	The control of INK4 box and p53 is closely related to the regulation of the aging process
24910096	Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear
24880050	Furthermore, expression of the p53 protein, an indicator of cell senescence and apoptosis, was elevated in adult and old SHR as well as in old WKY
24866151	Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer
24866151	Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53
24853424	In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21
24804545	PRIMA-1 selectively induces global DNA demethylation in p53 mutant-type thyroid cancer cells
24804545	The p53 tumor suppressor pathway blocks carcinogenesis by triggering apoptosis and cellular senescence in response to oncogenic stress
24804545	Over 50% of human cancers including thyroid cancer carry loss-of-function mutations in the p53 gene
24804545	Recently, the identification of mutant p53-reactivating small molecules such as PRIMA-1 (p53 reactivation and induction of massive apoptosis) renders possibilities for the development of more efficient anticancer drugs
24804545	Thus, this study uncovered a previously unrecognized and prominent biological effect of PRIMA-1 through which it can cause global DNA demethylation in p53 mutant-type cancer cells mainly by rescuing the function of mutant p53 protein
24797517	The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner
24797517	Here we show here that JMJD3 interacts with the tumour suppressor protein p53
24797517	Moreover, we find that JMJD3 binding sites show significant overlap with p53 bound promoters and enhancer elements
24797517	The binding of JMJD3 to p53 target sites is increased in response to DNA damage, and we demonstrate that the recruitment of JMJD3 to these sites is dependent on p53 expression
24797517	Therefore, we propose a model in which JMJD3 is recruited to p53 responsive elements via its interaction with p53 and speculate that JMJD3 could act as a fail-safe mechanism to remove low levels of H3K27me3 and H3K27me2 to allow for efficient acetylation of H3K27
24788960	With SA-beta-Gal staining, we show that Klf4(-/-) MEFs enter senescence earlier than Klf4(+/+) MEFs, and western blot shows accumulation of p21 and p53 with increasing passages
24752601	Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction
24752601	Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation
24747221	RESULTS: We found that acrolein induced cellular senescence by increasing both p53 and p21
24747221	Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition
24739573	However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well as communication within the tumour microenvironment
24739573	In this Opinion article, we discuss the roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression
24738879	Inhibition enhancer of zeste homologue 2 promotes senescence and apoptosis induced by doxorubicin in p53 mutant gastric cancer cells
24738879	CONCLUSIONS: These data help unravel a crucial role for EZH2 in senescence and apoptosis in gastric cancer cells and that p53 genomic status was associated with different cell responses to EZH2 silencing
24732589	Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53(+/-) or p53(-/-) background
24721210	The elevated apoptotic background of Gadd45alpha-/- cells is accompanied by higher levels of Ser15-phosphorylated p53 and p21/Waf1 proteins that additionally commit the cells to HDIs-induced apoptosis
24719353	Caveolin-1 and p53 expression was decreased in bone in SPI-fed, but not in 17beta-estradiol (E2)-treated rats
24719353	In cell culture studies, membranous caveolin-1 and nuclear p53 expression was greater in replicative senescent ST2 cell cultures than in earlier passaged cells
24719353	SPI-fed rat serum significantly down-regulated both caveolin-1 and p53 in senescent and nonsenescent cells
24719353	Replicative senescent ST2 cells exhibited a strong association among caveolin-1, p53, and mouse double minute 2 homologue (mdm2), which was inhibited by SPI-fed rat serum
24719353	Overexpression of caveolin-1 in ST2 cells resulted in increased expression of p53 and p21, whereas, knockdown of caveolin-1 using shRNA led to increases in mdm2 and eliminated SPI-fed rat serum's effects on p53 and p21 expression
24719353	In contrast, manipulation of caveolin-1 expression did not affect the actions of E2 or isoflavones on p53 expression in either ST2 or OB6 cells
24704832	Importantly, silencing of PRAS40 induces upregulation of p53 in a manner dependent on RPL11
24704020	TP53 allelic loss and mean expression of genes related to p53 dependent cellular senescence were compared
24704020	About half of the patients with PTEN biallelic loss had accompanying TP53 allelic loss
24704020	It does not seem to induce p53 dependent cellular senescence, partly due to allelic loss of TP53
24675459	Here we show that mice with chronic activation of p53 develop an aging phenotype in the skin associated with a reduction of subcutaneous fat and loss of sebaceous gland (SG)
24674756	PPM1B is a member of the protein phosphatase 2C family and plays a role in negatively regulating p53 and NF-kappaB thereby possibly attenuating the gene expression program of cellular senescence
24672805	The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53
24665044	A significantly higher number of senescent cells, over-expression of p53 and p21 were observed in the As-exposed individuals when compared to unexposed
24659628	With aging, p85alpha, IGF-1 and B-myb muscle levels were lower while the expression of certain cell arrest proteins (p53, p16 and pRB) increased
24658599	Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF)
24658599	The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation
24651677	En face staining revealed that senescence-associated beta-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet
24651677	By contrast, ECs exposed to undisturbed flow did not express senescence-associated beta-galactosidase or p53
24625975	These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70
24618719	Cancer cells can overcome the antiproliferative effects of excessive DNA damage by inactivating a DNA damage response pathway such as ATM or p53 signaling
24552809	Wip1 (protein phosphatase Mg(2+)/Mn(2+)-dependent 1D, Ppm1d) is a nuclear serine/threonine protein phosphatase that is induced by p53 following the activation of DNA damage response (DDR) signaling
24552809	In this study, we found that even at a representative physiological concentration of 3% O2, Ppm1d(-/-) MEFs underwent premature cellular senescence that depended on the functional activation of p53
24551275	Alveolar epithelial cells in idiopathic pulmonary fibrosis display upregulation of TRAIL, DR4 and DR5 expression with simultaneous preferential over-expression of pro-apoptotic marker p53
24551275	This upregulation was accompanied by pro-apoptotic protein p53 overexpression
24551275	In contrast, myofibroblasts within the fibroblastic foci of IPF lungs exhibited high TRAIL, DR4 and DR5 expression but negligible p53 expression
24551275	Similarly, p53 expression was absent or negligible in IPF and control alveolar macrophages and lymphocytes
24491427	In our study, to our knowledge, we first showed that IFI16 is a chromatin-binding protein in four HCC cell lines with different TP53 genotype, but not in fetal liver cell line, L02 cells
24490140	A novel cell-penetrating peptide derived from WT1 enhances p53 activity, induces cell senescence and displays antimelanoma activity in xeno- and syngeneic systems
24490140	Moreover, the peptide bound to p53 and competed with WT1 protein for binding to p53
24476133	We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and beta-galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS)
24462821	Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy
24462821	Activation of p53 can induce apoptosis, cell cycle arrest, and cell senescence, although some evidence has suggested that p53 could promote cell survival
24462821	However, whether p53 plays a positive role in cancer cell survival to chemotherapy remains unknown
24462821	Meanwhile, nutrient-deprivation-induced autophagy was inhibited by pifithrin-alpha or small interfering RNA targeting p53
24462821	This indicates that the basal level of p53 is important to autophagy activation in nutrient-deprived HCC cells
24462821	Furthermore, combining p53 inhibition and nutrient deprivation or 5-FU treatment resulted in a marked increase in reactive oxygen species generation and mitochondrial damage
24459734	Two classical tumor suppressors, p53 and pRB, control cell cycle arrest associated with senescence
24449267	Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence
24441872	This was associated with activation of the senescent pathway markers p53/21 and p16
24405415	The HUVECs treated with KP exhibited the senescent phenotype, as determined using a senescence-associated beta-galactosidase assay, cell morphology analysis, and decreased Sirt1 (sirtuin 1) expression and increased p53 expression shown by Western blot analysis
25946838	Peptide AED and EDL increase cell proliferation, decreasing expression of marker of aging p16, p21, p53 and increasing expression of SIRT-6 in young and aged renal cell culture
24361399	Cellular senescence was measured by SA-beta-gal staining and based on the protein expression of p53 and p21(Cip1/WAF1)
24361399	Finally, experiments using T47D (wild-type p53) and MDA-MB-435 (mutant p53) cell lines suggested that tamoxifen induces p53-independent ROS production as well as p53-dependent senescence in breast cancer cells
24356923	Studies on normal aging have identified a molecular circuit in which the dysfunction of telomeres caused by cellular aging activates the TP53 gene
24322375	Analysis of expression levels of p53, p21(CIP1), p16(INK4a), p27(KIP1), pRb and E2F1 and genetic knockdown of p21(CIP1) demonstrated an important role of p21(CIP1) in RD-triggered cellular senescence
24302615	The observed antitumor effects of NDRG1 suppression were correlated with activation of major senescence-associated signaling pathways, such as upregulation of tumor suppressors p53, p21 and p16, and decreased phosphorylated Rb
24272483	Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling
24264057	The emerging role of p53 in exercise metabolism
24264057	The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology
24264057	Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence
24264057	More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle
24264057	In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance
24264057	Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-alpha protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria
24264057	Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols
24264057	Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex
24264057	In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling
24264057	Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues
24264057	Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guidelines to strategically target p53 signalling
24264057	The emerging role of p53 in skeletal muscle metabolism therefore represents a novel and exciting research area for exercise and muscle physiologists
24253049	These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence
24231352	Here, we found that the endogenous p53 isoforms Delta133p53 and p53beta are physiological regulators of proliferation and senescence in human T lymphocytes in vivo
24223226	Interestingly, the protein levels of p21, a p53 target and well-known gene essential for the execution of cellular senescence, were upregulated in the presence of BCAAs
24205274	4 Gy/min) upregulated senescence markers including p53, p21/waf1, and senescence-associated beta galactosidase (SA-beta-gal)
24205274	Treatment with AG1024, an IGF-1R inhibitor, suppressed IR-induced upregulation of p53, p21/waf1, and SA-beta-gal
24205274	Together these findings suggest that IGF-1R is a key regulator of IR-induced accelerated senescence in a pathway that requires intact mTOR activity upstream of both p53 and p21/waf1
24198727	Both H(2)O(2) treatment and AdRas12V infection induced senescence in VECs, as assessed by senescence-associated beta-Gal activity and the expression of proteins such as p53 and p21(CIP1)
24186980	The fused cells activated the main molecular pathways of senescence, the p53- and p16-pRb-dependent pathways; the senescence-associated secretory phenotype; and immune surveillance-related proteins
24177958	The c-ABL non-receptor tyrosine kinase and the p53 tumor suppressor protein are pivotal modulators of cellular responses to DNA damage
24177958	When these cells were simultaneously treated with a c-ABL kinase inhibitor, STI571, or a c-ABL-specific siRNA along with adriamycin, the p53-dependent p21 induction was dramatically diminished, even though p53 is substantially induced
24170126	YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway
24169561	Furthermore, CRT knock-down suppressed the ovarian steroid-stimulated PRL and IGFBP1 expression and morphological differentiation, and silencing of EPAC2 or CRT significantly increased senescence-associated beta-galactosidase activity with enhanced p21 expression and decreased p53 expression
24151513	Numerous studies have shown that activation of the p53/p21 pathway inhibits the proliferation of BM-MSCs
24151513	The aim of this study was to determine whether p53/p21 pathway is involved in regulating the aging of BM-MSCs from SLE patients and the underlying mechanisms
24151513	The expressions of p53 and p21 were significantly increased, whereas levels of Cyclin E, cyclin-dependent kinase-2, and phosphorylation of retinoblastoma protein were decreased in the BM-MSCs from SLE patients and knockdown of p21 expression reversed the senescent features of BM-MSCs from SLE patients
24151513	Our results demonstrated that p53/p21 pathway played an important role in the senescence process of BM-MSCs from SLE
24130040	Wnt/beta-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway
24130040	We have found that Wnt/beta-catenin signaling and the p53/p21 pathway were significantly hyperactivated in senescent SLE BM-MSCs
24130040	Additionally, the expression levels of p53 and p21 were reduced in treated-SLE BM-MSCs compared with the untreated group
24130040	In summary, our study indicated that Wnt/beta-catenin signaling may play a critical role in the senescence of SLE BM-MSCs through the p53/p21 pathway
24124625	As a transcription factor, p53 responds to a variety of stresses to either induce apoptosis (cell death) or cell cycle arrest (cell preservation) to suppress tumor development
24124625	Yet, the effect p53 has on the non-cancer aspects of aging is complicated and not well understood
24124625	On one side, p53 could induce cellular senescence or apoptosis to suppress cancer but as an unintended consequence enhance the aging process especially if these responses diminish stem and progenitor cell populations
24124625	But on the flip side, p53 could reduce growth and growth-related stress to enable cell survival and ultimately delay the aging process
24124625	A better understanding of diverse functions of p53 is essential to elucidate its influences on the aging process and the possibility of targeting p53 or p53 transcriptional targets to treat cancer and ameliorate general aging
24122992	CONCLUSION: The absence of functional p16, pRB and p53 in DU145 suggests that Id4 could alter additional molecular pathways such as those involving E2F1 to promote senescence and increased sensitivity to doxorubicin-induced apoptosis
24094550	METHODS AND RESULTS: To investigate the molecular pathways of replicative cellular senescence, we first evaluated cellular senescence in ex vivo-expanded hCPC(c-kit+) by using senescence-associated beta-galactosidase (SA-beta-gal) activity with enlarged cytoplasm and observed increased expression of cell senescence-related pivotal molecules, including TP53, cleavage Mdm2 (cMdm2), and Mdm2
24094550	SA-beta-gal activity and cytoplasm size in senescent hCPC(c-kit+) were significantly reduced, with reduced TP53 and cMdm2 expression after treatment with a specific ERK inhibitor (U0126)
24074787	Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer
24074787	Recent findings may lead to reconsider the role of p53 in breast cancer
24074787	TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas
24074787	The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors
24074787	We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin-cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response
24074787	Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells
24074787	A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response
24074787	Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment
24074787	Conversely, in ER negative (ER(-)) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response
24074787	In view of these recent results, p53 impact in breast cancer should be reconsidered
24067722	Western blot analysis indicated lower levels of p53 and phospho-p53 (ser15) in HepG2 cells as compared to THLE2 cells; no significant changes in p53 or phospho-p53 (ser15) were noted with nevirapine treatment
24067722	The differential responses appear to be related to differences in the basal levels of p53 in the HepG2 cells and THLE2 cells
24067199	To investigate the effect of cisplatin on hepatocellular carcinoma, we treated HepG2 cells exhibiting wild-type TP53 with gradient concentrations of cisplatin
24065372	RESULTS: Dyskerin depletion induced early activation of the p53 pathway probably secondary to ribosome biogenesis failure
24065372	However, the p53 pathway in the fibroblasts from X-DC patients was activated only after an equivalent number of passes to AD-DC fibroblasts, in which telomere attrition in each division rendered shorter telomeres than control fibroblasts
24065372	Indeed, no induction of DNA damage was observed in dyskerin-depleted fibroblasts in contrast to X-DC or AD-DC fibroblasts suggesting that DNA damage induced by telomere attrition is responsible for p53 activation in X-DC and AD-DC fibroblasts
24065372	Moreover, p53 depletion in senescent DC fibroblasts rescued their proliferative capacity and reverted the morphological changes produced after prolonged culture
24065372	CONCLUSIONS: Our data indicate that ribosome biogenesis do not seem to play an important role in dyskeratosis congenita, conversely increasing DNA damage and activation of p53 pathway triggered by telomere shortening is the main activator of cell senescence
24052948	This is promoted by ATM and antagonized by p53
24052415	Also, in this group, Ki67 proliferation index correlated with a lower immunohistochemical expression of gammaH2AX and p53
24051088	However, in this study we found that adenosine treatment results in cellular senescence in A549 lung cancer cells both in vitro and in vivo; adenosine induces cell cycle arrest and senescence in a p53/p21 dependent manner; adenosine elevates the level of phosphor-gammaH2AX, pCHK2 and pBRCA1, the markers for prolonged DNA damage response which are likely responsible for initiating the cellular senescence
24043758	The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis
24043758	Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors
24043758	Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells
24043758	Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells
24043758	Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells
24041229	The interaction between FAK, MYCN, p53 and Mdm2 in neuroblastoma
24041229	This review focuses on the individual protein tyrosine kinase, focal adhesion kinase (FAK) and its interaction with the transcription factors, MYCN, p53, and Mdm2, and how their interactions modulate the growth and malignancy of neuroblastomas
24040275	The expression of key senescence regulators, especially p53, was significantly up-regulated in the infarcted heart or hypoxia-treated fibroblasts
24040275	Furthermore, knockdown of endogenous p53 by siRNA in fibroblasts markedly reduced hypoxia-induced cell senescence, cytokine expression but increased collagen expression, whereas increased expression of p53 protein by adenovirus infection had opposite effects
24040275	Consistent with in vitro results in cardiac fibroblasts, p53 deficiency in vivo significantly decreased the accumulation of senescent fibroblasts, the infiltration of macrophages and matrix metalloproteinases, but enhanced collagen deposition after myocardial infarction
24040275	In conclusion, these results suggest that the p53-mediated fibroblast senescence limits cardiac collagen production, and inhibition of p53 activity could represent a novel therapeutic target to increase reparative fibrosis and to prevent heart rupture after myocardial infarction
24023735	The p53 tumour suppressor is crucial for cancer development and therapy, but has been less amenable to therapeutic applications due to the complexity of its action, reflected in 66,000 papers describing its function
24023735	Here we provide a systematic approach to integrate this information by constructing a large-scale logical model of the p53 interactome using extensive database and literature integration
24009740	Loss of the osteogenic differentiation potential during senescence is limited to bone progenitor cells and is dependent on p53
24008732	Here we show that ING1 translocates to the mitochondria of primary fibroblasts and established epithelial cell lines in response to apoptosis inducing stimuli, independent of the cellular p53 status
24006061	These include measurement of senescence-associated beta-galactosidase activity (SA-beta-gal), senescence-associated heterochromatin foci (SAHFs), proliferative arrest, morphological changes, and expression and activity of proteins involved in the senescence process, such as p53 and Rb pathway proteins and secretory proteins
24000115	Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 microM treatments
25509352	Further investigations showed that the preparation increases transcriptional activity of p53 gene, increase autophagy level and induce weak adipogenic differentiation
23989658	Combined treatment of MTOR inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated GLB1 (beta-galactosidase) activity, which appear to result from a constant activation of TP53 and a restoration in the activity of retinoblastoma 1 protein (RB1)-E2F1
23982736	The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment
23982736	In addition, p53 siRNA transfection attenuated metformin-induced SA-beta-gal staining
23982736	Intriguingly, co-expression of SIRT1 and p53 dramatically reduced the levels of Ac-p53, however, low doses of metformin treatment partially reversed the effect of SIRT1 on p53 acetylation and elevated SA-beta-gal activity
23979016	In a p53(-/-) tumor-prone background, mIno80 haploinsufficiency favored the development of sarcomas
23969248	In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-beta-galactosidase staining together with downregulation of E2F target genes
23966171	The tumor suppressor p53 is a modulator of the IFN response that plays a role in virus-induced apoptosis and in IFN-induced senescence
23966171	Here we demonstrate that IFN treatment increases the levels of SUMOylated p53 and induces cellular senescence through a process that is partially dependent upon SUMOylation of p53
23966171	Similarly, we show that vesicular stomatitis virus (VSV) infection induces p53 SUMOylation, and that this modification favors the control of VSV replication
23966171	Thus, our study provides evidence that IFN signaling induces p53 SUMOylation, which results in the activation of a cellular senescence program and contributes to the antiviral functions of interferon
23952478	Furthermore, while UVB irradiation induced p53 reporter activation in KSC, morin significantly inhibited UVB-induced p53 reporter activation in KSC
23952478	In addition, mouse double minute 2 homolog (MDM2, p53 E3 ubiquitin protein ligase) inhibitor significantly increased the p53 reporter activation in the UVB-irradiated KSC, but morin decreased the MDM2 inhibitor-mediated increase in p53 reporter activation
23952478	On the contrary, ATM inhibitor did not affect the protective effect of morin in UVB irradiation-induced p53 reporter activation
23952478	Collectively, these findings suggest that morin could effectively enrich the p53 specific ligasing ability of MDM2 in UVB irradiation-induced p53 activation
23941874	Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53
23941874	This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs
23940580	Aged kidneys 6 weeks post-reperfusion also express higher levels of p53 and p21 compared to the young, correlating with greater increases in senescence associated (SA) beta-galactosidase, a known marker of cellular senescence
23940366	Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context
23940366	We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro
23940366	In contrast, GH is not induced in cells devoid of p53
23940366	Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells
23940366	In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver)
23940366	Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene
23934686	This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression
23933816	ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence
23933816	YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation
23933816	The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion
23933099	Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway
23933099	Collectively, our results demonstrated that simvastatin can induce senescence in human melanoma cells by activation of p53/p21 pathway, and that oxidative stress may be related to this process
23924947	In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis
23916530	The retinoblastoma protein (RB) and p53 tumor suppressors are central to the process and the growth arrest is primarily implemented by the cyclin-dependent kinase (CDK) inhibitors, p16INK4a and p21CIP1
23904845	No pathogenetic mutations in CDKN2A, BRAF, NRAS, KRAS, cKIT, TP53 and PTEN genes were observed
23897841	Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16(INK4a) (p16), and retinoblastoma (Rb)
23870914	Twenty-four hour treatment with debarked stems extract resulted in the strong induction of p53 and p16, whereas both leaf extracts inhibited the activation of ERK
23869868	Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage
23869868	As a key player during DNA damage response (DDR), p53 transactivates an array of target genes that are involved in various cellular processes including the induction of cellular senescence
23869868	Unexpectedly, we found that the upregulation of CXCR2 depends on the function of p53
23869868	Like other p53 target genes such as p21, CXCR2 is transactivated by p53
23869868	We identified a p53-binding site in the CXCR2 promoter that responds to changes in p53 functional status
23869868	Thus, CXCR2 may act downstream of p53
23869868	While the senescence-associated secretory phenotype (SASP) exhibits a kinetics that is distinct from that of CXCR2 expression and does not require p53, it reinforces senescence
23869868	Our results thus demonstrate CXCR2 as a critical mediator of cellular senescence downstream of p53 in response to DNA damage
23840802	We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD
23832324	Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability
23832324	In nonsenescent VSMCs, overexpressing wild-type Arg-II or an l-arginine ureahydrolase inactive Arg-II mutant (H160F) caused similar effects on mitochondrial dysfunction, cell apoptosis, and senescence, which were abrogated by silencing p66Shc or p53
23832324	The activation of p66Shc but not p53 by Arg-II was dependent on extracellular signal-regulated kinases (ERKs) and sequential activation of 40S ribosomal protein S6 kinase 1 (S6K1)-c-Jun N-terminal kinases (JNKs)
23832324	In senescent VSMCs, Arg-II and S6K1, ERK-p66Shc, and p53 signaling levels were increased
23832324	CONCLUSIONS: Arg-II, independently of its l-arginine ureahydrolase activity, promotes mitochondrial dysfunction leading to VSMC senescence/apoptosis through complex positive crosstalk among S6K1-JNK, ERK, p66Shc, and p53, contributing to atherosclerotic vulnerability phenotypes in mice
23830072	Reduced p53 binding to the promoter of the cell cycle checkpoint regulator p21 was also detected in cells cleared of infection and p21 levels were reduced; moreover, this cell population exhibited increased resistance to etoposide-induced DNA damage
23814485	A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation
23814485	These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling
23814485	To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis
23814485	Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence
23814485	These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression
23811199	The phosphorylation of p53 and histone H2Ax and the induction of the two proapoptotic genes Bax and Noxa were evident in SOD1-deficient MEFs and more enhanced under normoxic culture than under hypoxic culture
23811199	We concluded that low levels of oxygen consumption moderately activates the p53 pathway, and leads to cellular senescence, but that high levels of oxygen consumption hyperactivates the p53 pathway, which results in cell death in SOD1-deficient MEFs
23807740	Condurango-glycoside-A fraction of Gonolobus condurango induces DNA damage associated senescence and apoptosis via ROS-dependent p53 signalling pathway in HeLa cells
23807740	Expression of p53 was also up-regulated, indicating that apoptosis could have been mediated through p53 pathway
23807740	Expression profiles of certain relevant genes and proteins like p53, Akt, Bcl-2, Bax, cytochrome c and caspase 3 also provided evidence of ROS mediated p53 up-regulation and further boost in Bax expression and followed by cytochrome c release and activation of caspase 3
23807740	Overall results suggest that CGA initiates ROS generation, promoting up-regulation of p53 expression, thus resulting in apoptosis and pre-mature senescence associated with DNA damage
23788032	The knockdown of CPEB1 reduced cell senescence by regulating the expression or distribution of p53 in glioma cells
23776040	Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer
23776040	Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability
23773483	Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status
23766372	Here, we demonstrate that REGgamma-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1delta and p53
23766372	Interestingly, a massive increase of p53 in REGgamma(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced
23766372	Allelic p53 haplodeficiency in REGgamma-deficient mice attenuated premature aging features
23766372	Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1delta-Mdm2-p53 regulation in the cellular aging process
23764844	We show that gamma-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53
23764844	Although the main effector of the response to gamma-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1alpha (HIF1alpha) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1beta inhibition by HIF1alpha, thus promoting mitochondrial biogenesis
23758631	Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, because reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive beta-galactosidase activity, and heightened p53 levels
23744553	Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation
23744553	This study aimed to evaluate the link among 8-hydroxydeoxyguanosine, OGG1 polymorphism, telomerase activity, telomere length, and p53 mutation in Barrett progression
23744553	Serum samples were obtained for p53 mutation
23744553	RESULTS: Controls had significantly lower levels of 8-hydroxydeoxyguanosine and telomerase activity, with normal telomere length and no p53 mutation
23744553	In short-segment Barrett esophagus, 8-hydroxydeoxyguanosine levels were higher and telomeres underwent significant shortening, with stimulation of telomerase activity but no p53 mutations
23744553	In long-segment Barrett esophagus, 8-hydroxydeoxyguanosine reached maximal levels, with telomere elongation, and 42 % of the patients showed p53 mutation
23744553	CONCLUSIONS: In Barrett patients, with disease progression, oxidative DNA damage accumulates, causing telomere instability, telomerase activation, and, in a late phase, mutations in the p53 gene, thus abrogating its activity as the checkpoint of proliferation and apoptosis, and facilitating progression to cancer
23739040	Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer
23739040	BACKGROUND: p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence
23739040	TP53 is mutated in around 50% of human cancers
23739040	Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear
23739040	Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice
23739040	METHODS: By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome
23739040	Moreover, survival effects of CSNK1A1 together with p53 were also studied
23739040	Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue
23739040	RESULTS: Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0
23739040	Expression of CSNK1A1 modified p53 survival effects
23739040	Patients with low CSNK1A1 expression and non-functional p53 had a very poor survival both in the univariate (Log Rank p<0
23739040	CONCLUSION: The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients
23727633	Glucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence
23727633	Increased levels of acetylated p53 as well as increased RNA levels of its pro-senescence effector p21 were evident in dexamethasone-treated tenocytes
23727633	Levels of the p53 deacetylase sirtuin 1 were lower in dexamethasone-treated cells compared with controls
23727633	Knockdown of p53 or inhibition of p53 activity prevented dexamethasone-induced senescence
23719597	In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker alpha-smooth muscle actin (alpha-SMA), p53, Cdk1 and Rad54 was diminished
23710306	Senescence is activated through an interaction between the p16 and p53 tumor-suppressor genes
23691139	Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A
23690620	Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality
23690620	The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence
23690620	Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner
23690620	We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation
23690620	Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus
23690620	Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiation-induced mortality in vitro and in vivo
23690620	Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop
23656786	Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner
23656786	UNLABELLED: p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers
23656786	The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53 (wild-type/R172H) ) that recapitulates a frequent p53 mutation (p53 (R175H) ) in human sporadic and Li-Fraumeni cancers
23656786	KEY POINTS: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative / myelodysplastic overlap
23649808	In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM
23649808	Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation
23643076	The expressions of senescence-associated genes p16(INK4a);, p19(Arf);, p53, p21(Cip1/Waf1); mRNA were detected by RT-PCR
23637463	Thus, by inhibiting Nrf2-mediated signaling, caveolin-1 links free radicals to the activation of the p53/senescence pathway
23612976	Most of the effects of Wip1 may be attributed to its ability to dephosphorylate p53 at Ser(15) and to inhibit DNA damage response
23612976	However, we also uncover a regulatory pathway whereby suppression of p53 Ser(15) phosphorylation is associated with enhanced phosphorylation at Ser(46), increased p53 protein levels, and induction of Noxa expression
23612969	A novel p53 mutant found in iatrogenic urothelial cancers is dysfunctional and can be rescued by a second-site global suppressor mutation
23612969	Rare A-->T TP53 mutations were recently discovered in AA-associated urothelial cancers
23612969	There are no cell banks with established lines derived from human tumors with which to explore the influence of the novel mutants on p53 function and cellular behavior
23612969	To investigate their impact, we generated isogenic mutant clones by integrase-mediated cassette exchange at the p53 locus of platform (null) murine embryonic fibroblasts and kidney epithelial cells
23612969	The N131Y mutant demonstrated a phenotype akin to common tumor mutants, whereas Q104L clone behavior resembled that of cells with wild-type p53
23612969	Wild-type p53 responses were restored in double-mutant cells harboring N131Y and N239Y, a second-site rescue mutation, suggesting that pharmaceutical reactivation of p53 function in tumors expressing N131Y could have therapeutic benefit
23611899	To determine whether these effects were due to altered chondrocyte growth and survival, we assayed the expression of cell proliferation marker Ki67, cell cycle arrest markers p21 and p53, and apoptosis marker caspase 3
23579096	We treated cultured human mesangial cells with glycated albumin, one of the most abundant Amadori product, and senescence was assessed by determining the senescence associated beta-galactosidase activity and the expression of the cell cycle regulators p53 and p21
23578831	The mechanism of senescence control is believed to be related to the peptide's ability to reversibly downregulate ataxia telangiectasia mutated (ATM) and p53 protein expression
23578831	The importance of p53 as the gatekeeping protein for monitoring cellular DNA damage is strategic for maintaining cellular health
23578831	ATM activates p53 by direct phosphorylation, causing cells to move into senescence which effectively moves them out of reproductive processes
23578831	Technologies that can influence ATM and p53 expression may offer unique benefits for controlling cellular senescence and effectively delaying cellular aging processes
23578831	The influence on ATM and p53 expression is noted to occur in both cell lines at peptide concentrations between 0
23578198	Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells
23578198	Mechanistic investigations indicated that therapy-induced senescence (TIS) following sunitinib treatment mainly attributed to p53/Dec1 signaling activation mediated by Raf-1/NF-kappaB inhibition in vitro
23578198	Importantly, in vivo study showed tumor growth inhibition and prolonged overall survival were associated with increased p53 and Dec1 expression, decreased Raf-1 and Ki67 staining, and upregulated SA-beta-gal activity after sunitinib treatment
23578198	Taken together, our findings suggested that sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation via inhibited Raf-1/nuclear factor (NF)-kappaB activity
23562644	Non-cell-autonomous tumor suppression by p53
23562644	The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis
23562644	Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function
23557329	RESULTS: We observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways
23553737	Silencing the expression of p53 or p21 by lentivirus-mediated shRNA production in cells blocked the CCN1-induced senescence
23542362	Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and FOXO3, thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction
23536448	Cellular senescence induced under conditions of forced NPM1 suppression could be prevented by knocking down p53
23536448	The differential expression of NPM1 along the normal colon-adenoma-carcinoma progression and its involvement in resisting p53 related senescent growth arrest in CRC cell lines implicate its role in supporting CRC tumorigenesis
23531985	Exciting new data from our laboratory show that SIRT1 is upregulated in the kidneys of p66 null Akita mice and decreases acetylation of p53, which destabilizes the p53 protein and prevents the transcription of p53 proapoptosis genes
23516461	Culturing on Wharton's jelly extract delays mesenchymal stem cell senescence through p53 and p16INK4a/pRb pathways
23516461	Reactive oxygen species (ROS), p53, and p16INK4a/pRb expression increased with passaging
23516461	Analysis at the molecular level revealed that WJE-based culture efficiently suppressed the enhancement of intracellular ROS, p53, and p16INK4a/pRb in MSCs
23513067	Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension
23513067	BACKGROUND: Induction of cellular senescence through activation of the p53 tumor suppressor protein is a new option for treating proliferative disorders
23513067	Nutlins prevent the ubiquitin ligase MDM2 (murine double minute 2), a negative p53 regulator, from interacting with p53
23513067	In these mouse models of PH, Nutlin-3a markedly increased senescent p21-stained PA-SMCs; lung p53, p21, and MDM2 protein levels; and p21, Bax, PUMA, BTG2, and MDM2 mRNA levels; but induced only minor changes in control mice without PH
23513067	PH prevention or reversal by Nutlin-3a required lung p53 stabilization and increased p21 expression, as indicated by the absence of Nutlin-3a effects in hypoxia-exposed p53(-/-) and p21(-/-) mice
23510477	The purpose of this study was to investigate the effects of miR-34c on apoptosis and proliferation of dairy goat male germline stem cells (mGSCs), as well as to determine the relationship between p53 and miR-34c in this species
23486996	Compound In Vivo Inactivation of Pml and p53 Uncovers a Functional Interaction in Angiosarcoma Suppression
23486996	PML's many roles have been linked, at least in part, to its functional interaction with the tumor suppressor p53
23486996	It has been shown that PML favors both p53 accumulation and transcriptional activity; in turn, PML expression is directly regulated by p53, and this reciprocal regulation contributes to p53-mediated apoptosis and senescence
23486996	Here we show that complete Pml inactivation, in a context of p53 heterozygosity, redistributes and expands the tumor spectrum leading to the formation of angiosarcomas and increased lymphomagenesis
23486996	Importantly, we find that Pml inactivation decreases the rate of loss of heterozygosity (LOH) in the remaining p53 allele, revealing the relevancy of p53 haploinsufficiency to tumorigenesis
23478443	Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence
23478443	We report that the oncogenic splicing factor SRSF1, which is overexpressed in many cancers, stabilizes the tumor suppressor protein p53 by abrogating its MDM2-dependent proteasomal degradation
23478443	Consistent with the stabilization of p53, increased SRSF1 expression in primary human fibroblasts decreases cellular proliferation and ultimately triggers oncogene-induced senescence (OIS)
23478296	Engaging the p53 metabolic brake drives senescence
23478296	Emerging evidence suggests that the ability of p53 to regulate metabolism is important for its tumor suppressor activity
23478296	A recent study published in Nature reveals a novel connection between p53 and metabolism: p53 transcriptionally represses the expression of malic enzymes and associated NADPH production, which in turn triggers a positive feedback loop resulting in sustained p53 activation, cellular senescence, and tumor suppression
23451179	Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a), p21 and phosphorylated p53 (Ser15)
23448364	Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging
23448364	Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53
23448364	We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress
23448364	We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence
23438604	Consistently, knockdown of pRB, p21(CIP1), and p16(INK4a), but not p53, suppressed SAHF formation induced by BRG1
23430755	By double labeling of senescent cells, first by SA-beta-Gal and then by antibodies against genes related to cellular senescence, we found that p21, p16, and RARbeta, but not p53, were upregulated by bexarotene in mammary tumors and in breast cancer cell lines, suggesting involvement of multiple signaling pathways in mediating the senescence program of rexinoids
23430617	PGC-1alpha disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas
23423975	The endogenous Cdkn2a products p19(ARF) and p16(Ink4a) were activated by the transgenic p14(ARF) through p53, revealing a senescence-promoting feed-forward loop
23416979	Senescence and aging: the critical roles of p53
23416979	However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging
23416979	Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context
23392125	ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells
23392125	We report here that apoptosis-stimulating protein of p53 (ASPP) 1 and 2, two activators of p53, preferentially bind active RAS via their N-terminal RAS-association domains (RAD)
23392125	In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53
23385819	Adipocytes subjected to oxidative stress also showed shortened telomeres and increased mRNA and protein expression of p53, p21, TNF alpha and IL-6
23359450	Proliferation and differentiation potentials, oxidative stress, senescence and p53/p16 expressions have been examined
23359450	Most of the MSCs cultured under normoxic conditions ceased to proliferate after 20-28 PD, while few senescent cells were found in the hypoxic, PEDF-hypoxic and PEDF-normoxic cultures; this was associated with downregulation of p53 and p16 expression and decreased oxidative stress
23358854	Keratinocyte senescence acts as a barrier to tumor progression but appears to be lost in late pre-malignancy to yield genetically unstable oral squamous cell carcinomas (GU-OSCC); a subset of OSCC possessing wild-type p53 and are genetically stable (GS-OSCC)
23358854	Treatment of normal fibroblasts with keratinocyte conditioned media (CM) from GU-OSCC, but not GS-OSCC or dysplastic keratinocytes with dysfunctional p53, induced fibroblast senescence
23349028	Immunoblot analysis showed an activation of the p53/p21 pathway corresponding to the progressing senescence
23349028	Our data suggest that chronic radiation-induced DNA damage and oxidative stress result in induction of p53/p21 pathway that inhibits the replicative potential of HUVECs and leads to premature senescence
23334421	Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
23334421	The pre-eminent tumour suppressor p53 has an important role in the induction and maintenance of senescence, but how it carries out this function remains poorly understood
23334421	Here we describe a new mechanism by which p53 links these functions
23334421	We show that p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells
23334421	Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- and AMP-activated protein kinase-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation
23334421	Downregulation of ME1 and ME2 also modulates the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppresses senescence
23334421	Our findings define physiological functions of malic enzymes, demonstrate a positive-feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53
23324396	Using a high-content siRNA screening assay for cell morphology and proliferation measures, we identify 12 senescence-regulating kinases and determine their senescence marker signatures, including elevation of senescence-associated beta-galactosidase, DNA damage and p53 or p16 (INK4a) expression
23301705	Bcl2-family members and p53)
23296673	In addition to an obligatory proliferation arrest, senescent cells manifest various senescence markers: mTOR-mediated hypertrophic growth (cell size increase), cell flattening, senescence-associated beta galactosidase (SA-beta gal) staining, expression of negative cell cycle regulators p53, p21(Waf1) and p16(Ink4a), specific chromatin reorganization including DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), senescence-associated secretory phenotype (SASP) and other features
23278893	Further evidences of AzA anti-senescence effect were repression of p53 and p21, increase in type I pro-collagen and abrogation of the enhanced expression of growth factors, such as HGF and SCF
23272171	DEX co-treatment cells exhibited the decrease of DNA damage signaling pathway proteins, the lower expression of p53 and p21(CIP1), the lower cellular secretory program and down-regulation of NF-kappaB and its signaling cascade
23272087	This mechanism appears to preserve androgen induced autophosphorylation of ATM and phosphorylation of H2AX, lesion processing and repair pathway yet restrain ATM/CHK1/CHK2 and p53 signaling pathway
23262037	Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma
23262034	The p53 tumor suppressor is activated in response to cellular stresses to induce cell-cycle arrest, cellular senescence, and apoptosis
23262034	The p53 gene is inactivated by mutations in more than 50% of human tumors
23262034	In addition, tumor cells dampen p53 activities via overexpression of p53-negative regulators, in particular 2 structurally related proteins, Mdm2 and Mdm4
23262034	Given that Mdm2 and Mdm4 inhibit p53 activities to promote tumor development, small molecules and peptides were developed to abrogate the inhibition of p53 by Mdm proteins
23259030	Preventive effects of epigallocatechin-3-O-gallate against replicative senescence associated with p53 acetylation in human dermal fibroblasts
23259030	The involvement of Sirt1 and acetylated p53 was examined as an underlying mechanism for the senescence preventive activity of EGCG in HDFs
23259030	Furthermore, EGCG was found to prevent serial passage- and H(2)O(2)-induced senescence in HDFs by suppressing p53 acetylation, but the Sirt1 activity was unaffected
23253087	Senescence evasion in melanoma progression: uncoupling of DNA-damage signaling from p53 activation and p21 expression
23253087	Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence
23253087	Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53
23253087	Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas, defective p21 upregulation by p53 even when phosphorylated
23242809	Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity
23234142	The expressions of senescence-related genes such as p16, p53, p21, Rb, were detected by RT-PCR and the changes in ultramicro-morphology were observed by transmission electron microscopy
23229510	E235-mediated induction of senescence was not dependent on p21 or p53; however, p21 conferred protection against the growth inhibitory effects of E235
23229510	E235 also activated DNA damage response signaling, resulting in increased levels of Ser15-phosphorylated p53, gamma-H2AX, and phosphorylated checkpoint kinase 2 (Chk2), although E235 does not appear to cause physical DNA damage
23224247	SIRT1 inhibition reduced DNA repair and induced apoptosis, in part, through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 but not p53
23216904	Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including beta-galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16Ink4a
23216904	This suggests that Nox-generated ROS transduce senescence signals by activating the p53 and p16Ink4a pathway
23209608	Lack of p53 affects the expression of several brain mitochondrial proteins: insights from proteomics into important pathways regulated by p53
23209608	The tumor suppressor protein p53 has been described "as the guardian of the genome" for its crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, senescence, or apoptosis in response to various stress signals
23209608	Although p53 promotes longevity by decreasing the risk of cancer through activation of apoptosis or cellular senescence, several findings suggest that an increase of its activity may have deleterious effects leading to selected aspects of the aging phenotype and neurodegenerative diseases
23209608	There is the link between p53 and oxidative stress, the latter a crucial factor that contributes to neurodegenerative processes like Alzheimer disease (AD)
23209608	In the present study, using a proteomics approach, we analyzed the impact of lack of p53 on the expression of several brain mitochondrial proteins involved in different pathways, and how lack of p53 may present a target to restore neuronal impairments
23209608	Our investigation on isolated brain mitochondria from p53((-/-)) mice also provides a better understanding of the p53-mitochondria relationship and its involvement in the development of many diseases
23193674	Recent studies show that through adjusting the activity of endothelial nitric oxide syntheses (eNOS), p53, forkhead box class O (FOXO) and nuclear factor kappa B (NF-kappaB), SIRT1 can protect the functions of vascular endothelia and nerves in a variety of pathological conditions
23176571	The protein expression of p53 and p21 was significantly increased in KO-MEFs, and knockdown of p53 or p21 reversed CSE deficiency-induced senescence
23168260	We show that JMJD2A functions as a negative regulator of Ras-induced senescence and collaborates with oncogenic Ras to promote cellular transformation by negatively regulating the p53 pathway
23168260	The expression of JMJD2A inhibits Ras-mediated CHD5 induction leading to a reduced activity of the p53 pathway
23146670	During senescence, telomere shortening-generated DNA damage activates p53 pathway that upregulates cell cycle inhibitors, such as p21
23146670	Whereas doxorubicin treatment in early-passaged cells results in nucleosome density changes near the p53 binding sites of the p21 promoter, our studies show that senescent cells with a high p21 transcription activity had a comparable nucleosome distribution as unstressed young cells
23137536	The four miRNA mimics increased senescent-associated beta-galactosidase (SA-beta-gal) staining, p53 and p21(Cip1/WAF1) expression, and reactive oxygen species (ROS) production
23124852	After scavenging ROS with N-acetylcysteine, Wnt/beta-catenin signaling-induced MSC aging was significantly attenuated and the DNA damage and the expression of p16(INK4A), p53, and p21 were reduced in MSCs
23124483	Correlation of telomere length shortening with TP53 somatic mutations, polymorphisms and allelic loss in breast tumors and esophageal cancer
23124483	The present study was undertaken to investigate the potential interactions between p53 functional mutations, polymorphisms, allelic loss and telomere erosion in 126 breast tumor patients and 68 esophageal cancer patients
23124483	Somatic mutations, polymorphisms and allelic loss in the TP53 gene were detected by direct sequencing of both tumor and normal tissue samples
23124483	Our results showed that telomeres were significantly shorter in tumors with somatic p53 mutations compared with tumors with wild-type p53 in both breast tumors (P=0
23124483	Furthermore, TP53 allelic loss was detected and significantly associated with somatic mutations in both types of tumor tissues
23124483	These findings suggest that somatic p53 mutations, rs12951053 genotype CC and rs1042522 genotype GG contribute to erosion of telomeres, and TP53 allelic loss may be one of the representations of chromosomal instability caused by telomere erosion combined with somatic p53 mutations
23124483	These results support that the TP53 gene has a strong interaction with TL erosion in tumorigenesis
23091651	Centrosome aberrations associated with cellular senescence and p53 localization at supernumerary centrosomes
23091651	This study examines localization of p53 protein at centrosomes in mitotic cells, which is often observed in association with DNA damage response, to investigate a possible association between p53 localization and numerical centrosome aberrations induced by cellular senescence
23091651	Supernumerary centrosomes showed higher frequencies of p53 localization compared to normally duplicated centrosomes
23091651	Centrosome-associated p53 protein was phosphorylated at Ser15
23091651	These data suggest a possible association between localization of p53 protein and numerical centrosome aberrations in replicatively or prematurely senescent cells
23085987	Premature senescence, a key strategy used to suppress carcinogenesis, can be driven by p53/p21 proteins in response to various stresses
23069657	DNA damage-induced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats
23069657	The tumor suppressor p53 has an important role in inducing cell-intrinsic responses to DNA damage, including cellular senescence or apoptosis, which act to thwart tumor development
23069657	Whether DNA damage-induced p53 activity can contribute to senescence- or apoptosis-associated pro-tumorigenic inflammation is unknown
23069657	Recently, we generated a p53 knock-out rat via homologous recombination in rat embryonic stem cells
23069657	Here we show that in a rat model of inflammation-associated hepatocarcinogenesis, heterozygous deficiency of p53 resulted in attenuated inflammatory responses and ameliorated hepatic cirrhosis and tumorigenesis
23069657	Chronic administration of hepatocarcinogenic compound, diethylnitrosamine, led to persistent DNA damage and sustained induction of p53 protein in the wild-type livers, and much less induction in p53 heterozygous livers
23069657	Sustained p53 activation subsequent to DNA damage was accompanied by apoptotic rather than senescent hepatic injury, which gave rise to the hepatic inflammatory responses
23069657	These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, especially in livers exposed to agents that inflict lasting mutagenic DNA damage
23050148	Transcription of the Tumor Suppressor Genes p53 and RB in Lymphocytes from Patients with Chronic Kidney Disease: Evidence of Molecular Senescence
23050148	We wanted to investigate the transcription of the tumor suppressor genes p53 and RB to record, if these cells could be stimulated in vitro in order to divide, after the addition of antigenic and inflammatory factors
23050037	Furthermore, Ser15-phosphorylated p53 showed colocalization with the large foci
23050037	Since the treatment of senescent cells with phosphoinositide 3-kinase inhibitor, wortmannin, suppressed p53 phosphorylation, it is suggested that amplification of DNA damage signaling sustains persistent activation of ATM-p53 pathway, which is essential for replicative senescence
23049256	Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21(Cip1), induced by hydrogen peroxide
22981429	2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside ameliorates vascular senescence and improves blood flow involving a mechanism of p53 deacetylation
22981429	METHODS AND RESULTS: Oral administration of THSG for 14 weeks, resulted in notable increases in blood flow in spontaneously hypertensive rats (SHRs); and effective inhibition of vascular senescence as indicated by senescence-associated beta-galactosidase (SA-beta-gal) staining, phosphorylation of gammaH2AX observed by stain analysis of immunofluorescence, and K373 acetylation of p53 in the aortic arches of SHRs
22981429	THSG weekly activated SIRT1 activity, stimulated eNOS promoter reporter gene activity, and ameliorated H(2)O(2)-induced cellular senescence and K373 acetylation of p53 in cultured human umbilical vein endothelial cells (HUVECs)
22981429	CONCLUSIONS: THSG improves blood flow and ameliorates vascular senescence by increasing eNOS expression and Sirt1 activity and decreasing acetylation of p53 at K373 site, at least in part, both in vitro and in vivo
22917970	Most human cancers lose p53 function, yet all three proteins are capable of inducing apoptosis or cellular senescence
22917970	The p73 structure exhibits the same conserved architecture as p53 but displays a divergent L2 loop, a known site of protein-protein interaction
22917970	The loop in p73 is changed by a two-residue insertion that also induces repacking around the site of the p53 mutational hotspot R175
22917970	These results further highlight the structural variation that impacts p53 family interactions within the p53 interactome
22904064	Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor
22904064	PRMT6(-/-) MEFs displayed high transcriptional levels of p53 and its targets, p21 and PML
22904064	Generation of PRMT6(-/-); p53(-/-) MEFs prevented the premature senescence, suggesting that the induction of senescence is p53-dependent
22904064	Using chromatin immunoprecipitation assays, we observed an enrichment of PRMT6 and H3R2(me2a) within the upstream region of Trp53
22904064	Our findings define a new regulator of p53 transcriptional regulation and define a role for PRMT6 and arginine methylation in cellular senescence
22877754	IGF-I induced expression of a DNA damage marker, gammaH2AX, the increased levels of p53 and p21 proteins, and activated SA-beta-gal
22877754	In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-beta-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I
22868792	PGC-1alpha acts as a master regulator of energy metabolism and mitochondrial biogenesis and recent evidence shows that it interacts with p53 and telomerase
22847439	Suppression of geroconversion was p53- and HIF-1-independent, as hypoxia also suppressed geroconversion in cells lacking functional p53 and HIF-1alpha
22847439	Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR pathway and suppressed senescence caused by etoposide without affecting DNA damage response, p53/p21 induction and cell cycle arrest
22847439	Also hypoxia suppressed geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE)
22802529	The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence
22802529	Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways
22802529	We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target
22802529	Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways
22802145	Wt p53 impairs response to chemotherapy: make lemonade to spare normal cells
22802145	As published recently in Cancer Cell, p53 impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer
22802145	I discuss that, while treating tumors lacking wt p53, this phenomenon can be exploited to protect normal cells from chemotherapy because all normal cells have wt p53
22791394	Here, we report an important role for c-Abl in replicative senescence and immortalization by regulating the expression of two tumor suppressors that induce cellular senescence, p53 and p16(INK4a)
22791394	This resistance was attributed to premature senescence and reduced survival in senescent c-Abl (-/-) cells due to an increase in p16(INK4a) and p53 expression
22791394	Deleting p53 allows c-Abl (-/-) p53 (-/-) MEFs to bypass senescence to be spontaneously immortalized
22791394	Cell immortalization, but not senescence, was generally accompanied by mutations in p53 in both wildtype and c-Abl (-/-) MEFs, although the spectrum is different from that of human tumors
22783442	The expression of cyclin D1, Rb, maspin, p53 and mouse double minute 2 (MDM2) was analyzed in 20 paraffin-embedded tissue samples of normal oral mucosa (NOM), 14 samples of oral leukoplakia without dysplasia (OLD-), 11 samples of leukoplakia with dysplasia (OLD+) and 15 samples of oral squamous cell carcinoma (OSCC) by immunohistochemistry in tissue arrays
22783442	For the ARF-p53 pathway, the expression of p53 and MDM2 was significantly more frequent in the OLD- samples compared to in the NOM ones
22777358	Downregulation of splicing factor SRSF3 induces p53beta, an alternatively spliced isoform of p53 that promotes cellular senescence
22777358	Here, we show that SRSF3 regulates cellular senescence, a p53-mediated process to suppress tumorigenesis, through TP53 alternative splicing
22777358	Downregulation of SRSF3 was observed in normal human fibroblasts undergoing replicative senescence, and was associated with the upregulation of p53beta, an alternatively spliced isoform of p53 that promotes p53-mediated senescence
22777358	Knockdown of p53 partially rescued SRSF3-knockdown-induced senescence, suggesting that SRSF3 acts on p53-mediated cellular senescence
22777358	RNA crosslinking and immunoprecipitation assays (CLIP) also showed that SRSF3 in vivo binds to endogenous p53 pre-mRNA at the region containing the p53beta-unique exon
22777358	Splicing assays using a transfected TP53 minigene in combination with siRNA knockdown of SRSF3 showed that SRSF3 functions to inhibit the inclusion of the p53beta-unique exon in splicing of p53 pre-mRNA
22777358	These data suggest that downregulation of SRSF3 represents an endogenous mechanism for cellular senescence that directly regulates the TP53 alternative splicing to generate p53beta
22777358	This study uncovers the role for general splicing machinery in tumorigenesis, and suggests that SRSF3 is a direct regulator of p53
22744176	Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1)
22744176	However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice
22731250	SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity
22731250	RESULTS: Using a well characterized cholangiocarcinoma cell line we show that levels of SPRR2A expression, similar to that seen during stressful biliary wound repair responses, disrupts acetylation and subsequent p53 transcriptional activity
22731250	The p300 CH3 domain is essential for both the autoacetylation of p300 and transference of the acetyl group to p53 and HDAC1 is a component of several non-p300 complexes that enhance p53 deacetylation, ubiquitination, and proteosomal degradation
22731250	HDAC1 can also bind the p300-CH3 domain, regulating p300 acetylation and interfering with p300 mediated p53 acetylation
22731250	The importance of this pathway is illustrated by showing complete restoration of p53 acetylation and partial restoration of p300 acetylation by treating SPRR2A expressing cells with HDAC1 siRNA
22731250	CONCLUSION: Up-regulation of SPRR2A, similar to that seen during barrier epithelia wound repair responses reduces p53 acetylation by interfering with p300-p53 interactions and by increasing HDAC1 expression
22724383	P53, p21, Wnt3a, Wnt5a, sonic hedgehog (Shh) mRNA was detected by Real time polymerase chain reaction (PCR) and Wnt5a protein was determined by Western blot
22695319	The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53
22691188	Thus, deregulation of genes that control this process, like the tumor suppressor p53, may contribute to promoting cancer by allowing cells to bypass senescence
22691188	Necdin interacts with p53 and is also a p53 target gene, although the importance of Necdin in the p53 response is not clearly understood
22691188	However, we demonstrate that in normal human cells, Necdin expression mimicked the effect of p53 inactivation by increasing radioresistance
22691188	CONCLUSION: This result suggests that Necdin potentially attenuate p53 signaling in response to genotoxic stress in human cells and supports similar results describing an inhibitory function of Necdin over p53-dependent growth arrest in mice
22621437	Telomere-mediated defects in osteoblast differentiation are associated with increased p53/p21 expression and concomitant reduction in RUNX2
22621437	Conversely, MPCs from p53(-/-) mice do not have substantial telomere dysfunction and spontaneously differentiate into osteoblasts
22621437	These results suggest that critical telomere dysfunction may be a prominent mechanism for age-related osteoporosis and limits MPC differentiation into bone-forming cells via the p53/p21 pathway
22615843	Interferon-beta induces cellular senescence in cutaneous human papilloma virus-transformed human keratinocytes by affecting p53 transactivating activity
22615843	Indeed, experiments in gene silencing via specific siRNAs have shown that PML is essential in the execution of the senescence programme and that both p53 and p21 pathways are involved
22615843	IFN-beta treatment leads to a modulation of p53 phosphorylation and acetylation status and a reduction in the expression of the p53 dominant negative DeltaNp73
22615843	These effects allow the recovery of p53 transactivating activity of target genes involved in the control of cell proliferation
22613224	The SA-beta-galactosidase activation was observed both in p53+/+ and p53-/- cells, however the latter ones were less sensitive to the prosenescent activity of curcumin
22613224	Upregulation of p53 and p21 proteins was observed in p53+/+ HCT116, while p53-independent induction of p21 was noticed in p53-/- HCT116
22606351	Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence
22606351	Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways
22606351	CONCLUSIONS/SIGNIFICANCE: This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation
22596227	Efficient introduction of specific TP53 mutations into mouse embryonic fibroblasts and embryonic stem cells
22596227	This protocol describes a rapid, precise method for generating sets of embryonic stem (ES) cells or mouse embryonic fibroblasts (MEFs) harboring point mutations in the p53 tumor suppressor gene (officially known as Trp53)
22596227	The strategy uses cells from the Trp53 (p53-null) 'platform' mouse, which allows site-specific integration of plasmid DNA into the Trp53 locus
22596227	A library of cell lines expressing various p53 mutants derived from the same population of primary fibroblasts or platform ES cells can be acquired and screened in less than 1 month
22563078	58-kDa microspherule protein (MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates p53/p21 senescence pathway
22563078	MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence
22563078	First, MSP58 activates the DNA damage response and p53/p21 signaling pathways
22563078	Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21
22555846	Indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A through oxidative stress
22555846	IS increased the mRNA expression of p53 and p21 in HASMCs, whereas it did not change that of p16 and retinoblastoma protein (pRb)
22555846	The IS-induced expression of p53 and p21 was suppressed by N-acetylcysteine, an antioxidant
22555846	IS promoted protein expression of p53, p21, and senescence-associated beta-galactosidase (SA-beta-gal) activity in HASMCs, and N-acetylcysteine and pifithrin-alpha,p-nitro, a p53 inhibitor, blocked these effects
22555846	Administration of IS to hypertensive rats increased expression of SA-beta-gal, p53, p21, prelamin A, and oxidative stress markers such as 8-hydroxyl-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in the cells embedded in the calcification area of arcuate aorta
22555846	Further, the uremic rat model showed positive staining for SA-beta-gal, p53, p21, prelamin A, 8-OHdG, and MDA in the cells embedded in the calcification area of arcuate aorta, whereas AST-120 reduced the expression of these biomarkers
22555846	Taken together, IS accelerates vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A and downregulation of FACE1 through oxidative stress
22555620	Finally, we demonstrated that bone cell senescence is associated with decreased Sirt1 expression and activated p53, p16, and p21
22548705	We now attempted to define the molecular mechanisms leading to p53 activation in this model, and to identify effectors of Cyclin D1-induced senescence
22548705	RESULTS: Senescence evolved over a period of weeks, with initial hyperproliferation followed by cell cycle arrest due to ROS production leading to activation of a DNA damage response and the p53 pathway
22548705	We found that the p53 pathway was intact in tumors arising in a p18Ink4c-/- background, indicating that the two genes represent distinct tumor suppressor pathways
22548705	Upon tumor progression, both p18Ink4c-/- and p53-/- tumors showed increased Cdk2 expression
22548705	CONCLUSION: Our findings indicate that the p53 and the RB pathways play temporally distinct roles in senescence induction in Cyclin D1-expressing cells, and that Cdk2 inhibition plays a role in tumor suppression, and may be a useful therapeutic target
22513787	Specifically, we analyzed effectors of senescence, including p16(INK4a), p53, and DNA damage (gamma-H2AX), as well as predictive markers of senescence including Ki67, PML, senescence-associated beta-galactosidase, heterochromatic foci (H3K9Me, 4'-6-diamidino-2-phenylindole), and nuclear size
22508983	Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53
22497596	Moreover, dependent on the context they can exert tumor suppressor activities that cooperate with p53
22496421	However, activation of either the p53 or pRB tumor suppressor pathway was sufficient to induce lamin B1 loss
22480653	Notably, several tumour suppressors, such as p53, pRb or p16(Ink4a), play key roles both in the initiation of the senescence program and in its maintenance, which often involves epigenetic changes
22473749	Deletion of STAT3 prevented IL-22-induced HSC senescence in vitro, whereas the overexpression of a constitutively activated form of STAT3 promoted HSC senescence through p53- and p21-dependent pathways
22473749	Immunoprecipitation analyses revealed that SOCS3 bound p53 and subsequently increased the expression of p53 and its target genes, contributing to IL-22-mediated HSC senescence
22431922	Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence
22431922	Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2) as a p53-inducible senescence-associated gene
22431922	Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation
22403609	All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity
22392074	Two shRNA plasmid vectors against p21 or p53 gene were constructed and stably transfected into the MCF-7 cells to determine the involvement of p21 or p53 in cellular senescence induced by IGFBP-rP1
22392074	Knockdown of p53 in MCF-7 cells did not influence the growth inhibition, cellular senescence, and p21 expression of the cells in response to IGFBP-rP1 transfection
22374671	Stimulating TIG3 fibroblast cells with IL6/sIL6R sequentially caused an increase in reactive oxygen species (ROS) as early as day 1, followed by the DNA damage response, p53 accumulation and, finally, senescence on days 8-10
22359668	Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling
22359342	This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein
22359342	We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53
22355043	In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice
22355043	Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes
22353808	Soft-agar colony formation assay and nude mice xenograft experiments demonstrated that these cells, even those with additional inactivation of p53, did not have transformed phenotypes
22348305	Bach1-mediated suppression of p53 is inhibited by p19(ARF) independently of MDM2
22348305	The p19(ARF)-Bach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19(ARF)-MDM2 pathway
22333593	In human fibroblasts acutely exposed to oncogenic ras, pRb has a specific role in suppressing DNA replication, and p107 or p130 cannot compensate for the loss of this function; however, a second p53/p21-dependent checkpoint prevents escape from growth arrest
22333593	This model of oncogene-induced senescence requires the additional loss of p53/p21 to explain selection for preferential loss of pRb function in human malignancies
22333593	In two malignant human breast cancer cell lines, we found that individual RB family proteins were sufficient for the establishment of p16-initiated senescence, and that growth arrest in G 1 was not dependent on the presence of functional pRb or p53
22333593	Thus, under these circumstances, despite the presence of functional p53, p107 and p130 were unable to completely compensate for pRb in mediating senescence induction
22285491	ARF is the second most commonly inactivated tumor suppressor behind p53
22285491	In addition, RUVBL2 down-regulates the levels of p53 in an ARF-dependent manner
22248729	The senescence-associated protein p53 was also detected by Western blot
22233735	METHODS: We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14Arf and used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis
22233735	Western-blot analysis identified an increase of the p53 level as the most likely reason for the increased activity of its downstream markers BAX and p21
22233735	We were able to show that in most fibroids analyzed a higher sensibility than that of matching myometrium was noted with a corresponding increase of the p53 immunopositivity of the fibroid samples compared to those from myometrium
22223356	MCF-10A cells morphologically transformed by long-term exposure to AlCl(3) display strong upregulation of the p53/p21(Waf1) pathway, a key mediator of growth arrest and senescence
22217266	STAT1 knockdown using RNA interference significantly inhibited the progression of HMC senescence and decreased the elevated expression of p53 and p21(Cip1)
22217266	Our results indicate that STAT1 is implicated in the mediation of Ang II-induced HMC senescence through p53/ p21(Cip1) pathway, and that losartan could attenuate HMC senescence by regulating STAT1
23552604	The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development
23552604	However, very little is known about the physiological mediators of cellular senescence induced by p53
23552604	Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway
23552604	These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53
22200425	Further, it promotes the expression of p53 by ROS-induced activation of nuclear factor kappa B, thereby accelerating senescence of proximal tubular cells with progression of CKD
22200425	Administration of indoxyl sulfate to hypertensive rats reduces renal expression of Klotho and promotes cell senescence, with expression of senescence-associated beta-galactosidase, p53, p21, p16, and retinoblastoma protein, accompanied by kidney fibrosis
22200425	It promotes cell senescence, with expression of senescence-associated beta-galactosidase, p53, p21, p16, and retinoblastoma protein, in the aorta of hypertensive rats
22200421	Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity
22200421	N-acetylcysteine, an antioxidant, and pifithrin alpha p-nitro, a p53 inhibitor, were used to determine the role of reactive oxygen species (ROS) and p53 in the induction of cell senescence
22200421	Thus, both IS and ADMA induced endothelial senescence through ROS and p53
22200421	CONCLUSION: IS induces endothelial cell senescence by increasing ROS production and p53 activity, like ADMA
22193460	The STAT1 and STAT3 activity and the expression of p53 and p21(Cip1) were increased after Angiotensin II and H(2)O(2) treatment
22190494	Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53
22178470	SIRT1 regulates inflammaging via regulating forkhead box class O 3, p53, nuclear factor kappa B, histones and various proteins involved in DNA damage and repair
22170163	IMR90 cells showed typical features of senescent cells, like senescence-associated (SA) beta galactosidase expression, including up-regulation of p53 and p14ARF proteins and of p21(waf1) as well, but not of p16(INK4A) cyclin-dependent kinase (Cdk) inhibitor
22155925	The effects of LB1 silencing on proliferation require the activation of p53, but not pRb
22155925	However, the induction of premature senescence requires both p53 and pRb
22140513	Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function
22140513	This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence
22128747	The effects of exogenous human telomerase reverse transcriptase expression, p53 knockdown, disruption of the pRb pathway by over-expression of CDK4 and reduced oxygen concentration on the lifespan of primary HCEC were evaluated
22128747	We provide proof-of-principle that forced expression of telomerase, when combined with either p53 knockdown or CDK4 over-expression, is sufficient to produce immortalized HCEC lines
22119379	After H(2)O(2) exposure, the expression levels of p53 and p21 were increased in NHDF cells and pretreatment with AA-2G inhibited this increase
22117195	MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs
22117195	The promyelocytic leukemia (PML) tumor suppressor is a regulator of p53 acetylation and function in cellular senescence
22117195	Here, we demonstrate that MageA2 interferes with p53 acetylation at PML-nuclear bodies (NBs) and with PMLIV-dependent activation of p53
22117195	These results correlate with a reduction in NBs number and an impaired p53 response
22101268	Increased sensitivity of Bmal1(-/-) cells to oxidative stress was p53 independent and correlated with the disrupted regulation of reactive oxygen species (ROS) homeostasis in BMAL1 deficient cells: indeed, circadian oscillations of ROS level can be induced in wild-type but not in Bmal1(-/-) cells
22095030	Regulation of p53 by ING family members in suppression of tumor initiation and progression
22095030	However, the best known function of ING proteins is their cooperation with p53 tumor suppressor protein in tumor suppression
22095030	All major isoforms of ING family members can promote the transactivition of p53 and the majority of them are shown to directly interact with p53
22095030	In addition, ING proteins are thought to interact with and modulate the function of auxiliary members of p53 pathway, such as MDM2, ARF , p300, and p21, indicating their widespread involvement in the regulation and function of this prominent tumor suppressor pathway
22095030	It seems that p53 pathway is the main mechanism by which ING proteins exert their functions
22095030	Nevertheless, regulation of other pathways which are not relevant to p53, yet important for tumorigenesis such as TGF-beta and NF-kappaB, by ING proteins is also observed
22095030	This review summarizes the current understanding of the mutual interactions and cooperation between different members of ING family with p53 pathway and implications of this cooperation in the suppression of cancer initiation and progression
22086179	While protein levels of p53 were not altered upon MsrA deficiency, its acetylation level was significantly elevated, which subsequently activated p21 transcription
22073591	A tumor suppressor, p53, has been reported to function as a governing center to defend against these malignant transformations
22073591	Here we review how p53 cooperate with adverse stresses to drive cellular senescence, providing a framework for intricate molecular cross-talks
22068052	In addition to acting as a transcriptional cofactor for p53, ASPP1 has been shown to function in the cytoplasm to regulate the nuclear localization and activity of YAP/TAZ
22068052	We show here that the ability of ASPP1 to activate YAP results in the decreased expression of LATS2, which lowers the ability of p53 to induce p21, cell-cycle arrest and senescence
22068052	These activities of cytoplasmic ASPP1 in opposing p53-mediated p21 expression are in contrast to the role of nuclear ASPP1 in cooperating with p53 to induce the expression of apoptotic target genes, and may help to dampen p53 activity in normal cells
22067611	P16/p53 expression and telomerase activity in immortalized human dental pulp cells
22067611	Also examined were the expression of genes involved in proliferation and mineralization such as human alkaline phosphatase (ALP), beta-actin, collagen 1 (col-1), core binding factor (cbfa-1), dentin matrix protein (DMP-1), dentin sialophosphoprotein (DSPP), GAPDH, hTERT, osteocalcin (OCN), osteopontin (OPN) as well as oncoproteins involved in senescence (p16, p21 and p53) using RT-PCR
22052190	POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) inhibits endothelial cell senescence through a p53 dependent pathway
22052190	Knockdown of PATZ1 in young cells accelerated premature EC senescence, which was confirmed by growth arrest, increased p53 protein level and senescence-associated beta-galactosidase (SA-beta-gal) activity, and repression of EC tube formation
22052190	Cellular senescence induced by PATZ1 knockdown in young cells was rescued by knockdown of p53, but not by knockdown of p16(INK4a)
22037160	Oncogenic stress induces at least three intrinsic pathways, p16/pRb-, Arf/p53/p21- and the DNA damage response (DDR)-pathways, that induce premature senescence if the stress exceeds a threshold level
22025288	While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control
22022534	In cell lines with incomplete responses to p53, this shift may be difficult to document because of a high proportion of proliferating cells contaminating arrested (quiescent and senescent) cells
22022534	METHODOLOGY: During induction of senescence by low levels of endogenous p53 and ectopic p21, cells were co-treated with nocodazole, which eliminated proliferating cells
22020331	The B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and a downstream target of p53
22019631	In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS)
22019631	On the other hand, recent studies have revealed a pro-oxidant role for p53 by which cellular ROS are increased by enhanced transcription of proapoptotic genes
22010578	Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16(INK4A) and promyelocytic leukemia protein (PML) in normal cells
22010578	The cellular levels of p16(INK4A) and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16(INK4A), but not p53 rescued senescent cells from growth arrest
21980403	Senescence is a robust cell cycle arrest controlled by the p53 and Rb pathways that acts as an important barrier to tumorigenesis
21979375	Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells
21979375	We found that NF-kappaB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined
21979375	In cultured fibroblasts, NF-kappaB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence
21968188	We have previously shown that p53 activation is necessary for CKII inhibition-mediated cellular senescence
21968188	Here, CKII inhibition induced acetylation of p53 at K382 in HCT116 and HEK293 cells
21968188	These results reveal that CKII downregulation induces p53 stabilization by negatively regulating SIRT1 deacetylase activity during senescence
21930934	Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification
21930934	Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is the most ancient member of the ASPP family of proteins and an evolutionarily conserved inhibitor of p53
21927031	The transformed phenotype of E6AP-deficient MEFs is associated with lower basal and stress-induced accumulation of p53
21909130	AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy
21909130	We demonstrate that AKT-induced senescence is p53-dependent and is characterised by mTORC1-dependent regulation of p53 translation and stabilisation of p53 protein following nucleolar localisation and inactivation of MDM2
21909130	Furthermore, our data imply that chronic activation of AKT signalling provides selective pressure for the loss of p53 function, consistent with observations that PTEN or PIK3CA mutations are significantly associated with p53 mutation in a number of human tumour types
21909125	H2O2 (100 mumol/L) significantly decreased Sirt1 expression, and induced up-regulation of p53 acetylation and p16(INK4a), which were blocked by pre-treatment with RHL (10 mumol/L)
21909125	The expression of apoptosis-associated proteins, such as p53, p21, Bcl-2, and Bax, did not significantly change in the presence of H(2)O(2) (100 mumol/L) or RHL (10 mumol/L)
21872575	The expressions of p53 and p21, which contribute to vascular senescence, were also increased
21872575	Furthermore, p53 siRNA and p21 siRNA transfection attenuated adriamycin-induced SA-beta-gal staining
21852385	We set out to characterize the radiosensitizing effects of the tyrosine kinase inhibitor erlotinib and the monoclonal antibody cetuximab in NSCLC cells that contain wild-type p53
21852385	Senescence was completely dependent on wild-type p53 and associated with a reduction in cell number as well as impaired clonogenic radiation survival
21852385	Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53, where it is associated with an induction of p16
21852385	Interestingly, senescence and radiosensitization were linked to an increase in residual radiation-induced DNA double-strand breaks irrespective of p53/p16 status
21843507	Here, we show that ATRA induces promoter hypomethylation of p16 and p21 via down-regulation of DNA methyltransferases 1, 3a, and 3b to facilitate binding of Ets1/2 to the p16 promoter and p53 to the p21 promoter, resulting in up-regulation of their expression and subsequent induction of cellular senescence in HepG2 cells
21839870	Two classical tumor suppressors, p53 and pRB, control cell cycle arrest associated with senescence
21835799	The repression of both was previously shown to result in activation of their respective tumor suppressor targets, p53 and pRb, and subsequent senescence induction in cervical cancer cells
21832251	We previously demonstrated that indoxyl sulfate induces senescence and dysfunction of proximal tubular cells by activating p53 expression
21832251	Inhibitors of NF-kappaB (pyrrolidine dithiocarbamate and isohelenin) and NF-kappaB p65 small interfering RNA (siRNA) suppressed indoxyl sulfate-induced senescence-associated beta-galactosidase activity and expression of p53, transforming growth factor (TGF)-beta1, and alpha-smoothe muscle actin (SMA)
21832251	The induction of p53 expression and p53 promoter activity by indoxyl sulfate were inhibited by pifithrin-alpha, p-nitro, an inhibitor of p53, whereas p53-transfected cells showed enhanced p53 promoter activity
21811608	METHODOLOGY/PRINCIPAL FINDINGS: Here we show that depletion of Tpr by RNA interference triggers G0-G1 arrest and ultimately induces a senescent-like phenotype dependent on the presence of p53
21784712	Important findings included significant upregulation of p53 and several proapoptotic genes (including apoptosis-inducing factor, mitochondrion-associated 1, BCL2-like 11 [an apoptosis facilitator]; caspase 7 apoptosis-related cysteine peptidase; proteasome 26S subunit nonadenosine triphosphatase 10, programmed cell death 6, and reticulon 3)
21765468	Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function
21765468	The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence
21764762	Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2
21764762	Although, both pathways activate p53, the relationship of p53 activation to upregulation of NKG2D ligands has not been addressed
21764762	In this study, we report that induction of wild-type p53, but not mutant p53, strongly upregulated mRNA and cell surface expression of ULBP1 and -2, whereas expression of other NK cell ligands was not affected
21764762	We defined intronic p53-responsive elements in these two novel p53 target genes
21764762	Taken together, our findings define the involvement of p53 in the regulation of specific NKG2D ligands that enhance NK cell-mediated target recognition
21764762	One implication of our work is that activating p53 after adoptive transfer of NK cells might constitute an effective combinatorial strategy of NK cell-based immunochemotherapy in cancers in which wild-type p53 function is preserved
21764698	OBJECTIVE: To investigate the role of lycium bararum polysaccharides (LBP) on angiotensin II (AngII)-induced senescence of human umbilical vein endothelial cells (HUVECs) and expressions of P53 and P16 and explore the mechanism of LBP against aging
21764698	Western blotting was employed to detect the expression of P53 and P16 in the exposed cells
21764698	The expression levels of P53 and P16 were significantly increased in the cells with AngII exposure (P<0
21764698	LBP treatment also increased the cell viability and significantly decreased the expression levels of P53 and P16 (P<0
21740549	An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence
21740549	The primary screen identified 112 known genes including p53 and another 29 shRNAmirs targetting as yet unidentified loci
21736542	The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb, whose expression is controlled by two distinct proteins, p19(Arf) and p16(Ink4a), respectively, which are encoded by the cdkn2a locus
21718309	Translational approaches targeting the p53 pathway for anti-cancer therapy
21718309	The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage
21718309	Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells
21718309	Different strategies exist that are adapted to the mechanisms of p53 inactivation
21718309	In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gene therapy is now practised in China
21718309	Also, remarkable progress has been made in the development of p53-binding drugs that can rescue and reactivate the function of mutant or misfolded p53
21718309	Inactivation of wt-p53 frequently results from dysregulation of MDM2, an E3 ligase that regulates p53 levels
21718309	Small-molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials
21718309	This survey highlights the recent developments that attempt to modulate the function of p53 and outlines strategies that are being investigated for pharmacological intervention in the p53 pathway
21703418	The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (DeltaN) the transactivation domain
21703418	In salivary gland cells, high expression of DeltaNp63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status
21702981	Suppression of CK2alpha by small-interfering RNA or the CK2alpha activity inhibitor emodin inhibited proliferation of CRC cells, caused G0/G1 phase arrest, induced cell senescence, elevated the expression of p53/p21 and decreased the expression of C-myc
21695255	Combining dysregulated beta-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence
21671470	Estrogen repression of YPEL3 expression was found to be independent of p53 but dependent on estrogen receptor alpha expression
21671044	Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere
21628992	Cellular senescence is a tumor-suppressive process instigated by proliferation in the absence of telomere replication, by cellular stresses such as oncogene activation, or by activation of the tumor suppressor proteins, such as Rb or p53
21628992	In this study, we demonstrate that p41-Arc can induce senescent phenotypes when it is overexpressed in human tumor cell line, SaOs-2, which is deficient in p53 and Rb tumor suppressor genes, implying that p41 can induce senescence in a p53-independent way
21628992	Therefore, these results imply that a change in actin filament can trigger an intrinsic senescence program in the absence of p53 and Rb tumor suppressor genes
21618508	To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab-associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53
21616554	Further examination revealed increased expression levels of senescence-associated genes such as p16, p21, p53, and caveolin in these cells along with a reduced proliferation rate
21594579	Given the important role of the ARF/p53 pathway in cellular senescence and tumor suppression, drugs that stabilize p53 expression have been developed and tested in clinical trials
21594579	However, a major hurdle for p53 targeting in cancer treatment arises from the frequent deficiency or mutation of ARF or p53 in human cancers, which, in turn, profoundly compromises their tumor-suppressive ability
21575166	CONCLUSION: Examining almost all known human micro-RNA species confirmed the miR-371-373 cluster as a promising target for explaining cisplatin resistance, potentially by counteracting wild-type P53 induced senescence or linking it with the potency to differentiate
21536657	IL-6-promoted entry into senescence requires p53; CPEB knockout MEFs, however, synthesize only approximately 50% of the p53 of wild-type MEFs, which is insufficient to respond to IL-6
21535365	This senescent phenotype was accompanied by engagement of the p53 tumor suppressor and induction of the p53 target gene p21 and was prevented by small hairpin RNAs against p53, p21, or by the oncoprotein Mdm2
21535365	The expression of E2F target genes, normally required for cell cycle progression, was downregulated after lamin A/C depletion but restored after the inactivation of p53
21535365	We thus reveal a previously unnoticed mechanism of controlling cell cycle genes expression, which depends on p53 but does not require the retinoblastoma family of tumor suppressors and that can be relevant to understand the pathogenesis of laminopathies and perhaps aging
21522127	USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1
21522127	In this study, we identified ubiquitin-specific peptidase 4 (USP4) as an important regulator of p53
21522127	USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels
21522127	Compared with wild-type mouse embryonic fibroblasts (MEFs), Usp4-/- MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4
21518927	Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer
21518927	A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways
21518927	This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway
21518171	Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9
21507983	Levels of the p53 tumor suppressor were elevated under conditions of JunD inhibition
21500551	Gamma-H2AX and phosphorylated P53 protein were measured by Western blot
21500551	Intra-cellular levels of gamma-H2AX and phosphorylated P53 protein were significantly increased in high glucose groups
21500551	KU55993, an inhibitor of ATM, significantly reduced the levels of gamma-H2AX, phosphorylated P53 protein, and positive rate of senescence-associated beta-galactosidase staining
21483692	Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme
21483692	Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells
21483692	Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status
21483692	In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence
21483692	Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug
21478871	CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation
21478871	Because CPEB regulation of p53 mRNA polyadenylation/translation is necessary for cellular senescence in primary human diploid fibroblasts, we surmised that Gld2 would be the enzyme responsible for poly(A) addition
21478871	Here we show that depletion of Gld2 surprisingly promotes rather than inhibits p53 mRNA polyadenylation/translation, induces premature senescence and enhances the stability of CPEB mRNA
21478871	Gld4, a second non-canonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner
21478871	Thus, translational regulation of p53 mRNA and cellular senescence is coordinated by Gld2/miR-122/CPEB/Gld4
21471201	These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent SCC cells via Bfl-1/A1 in the absence of functional p53
21468560	This study confirms that AngII induces the shortening of telomere lengths, P53 and P21 expression, cell cycle arrest, and the resulting cell senescence in GMCs
21464199	Cyclopentenyl cytosine induces senescence in breast cancer cells through the nucleolar stress response and activation of p53
21464199	We have demonstrated that depletion of CTP induced by cyclopentenyl cytosine (CPEC; NSC 375575), a specific inhibitor of the enzyme CTP synthetase, induces irreversible growth arrest and senescence characterized by altered morphology and expression of senescence-associated beta-galactosidase activity in MCF-7 breast cancer cells expressing wild-type p53
21464199	In contrast, differentiation in the absence of senescence resulted from CPEC treatment in MDA-MB-231 breast cancer cells that express a mutated p53
21464199	This nucleolar stress response resulted in a sustained elevation of p53 and the p53 target genes, p21 and Mdm2, in cells with wild-type p53
21464199	Furthermore, short interfering RNA-induced knockdown of p53 in MCF-7 cells treated with CPEC prevented cellular senescence and increased apoptotic cell death
21464199	We conclude that CTP depletion and the resulting nucleolar stress response results in a senescence-like growth arrest through activation of p53, whereas cells with mutated p53 undergo differentiation or apoptotic cell death
21456046	To see if p14(Arf) can repress HMGA2 by a TP53-dependent mechanism, nutlin-3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta-galactosidase, but also decreased the expression of HMGA2, suggesting that p14(Arf) indeed influences HMGA2 by a p53-dependent mechanism because nutlin-3 stabilizes p53
21456046	As to the interaction between HMGA2 and p14(Arf) in benign tumorigenesis, we propose a model where akin to MSC self-renewal during tissue repair the simultaneous increase of p14(Arf) with HMGA2 ensures genomic stability, whereas in turn p14(Arf) can repress HMGA2 via TP53
21445100	Taken together, our findings identify PTRF as a novel regulator of cellular senescence that acts through the p53/p21 and caveolar pathways
21406393	The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin and nuclear factors of activated T-cell signaling inhibits expression of ATF3, a negative regulator of p53
21402054	Loss of p21(Sdi1) expression in senescent cells after DNA damage accompanied with increase of miR-93 expression and reduced p53 interaction with p21(Sdi1) gene promoter
21402054	Induction of miR-93 expression and reduced p53 binding to p21 gene promoter account for loss of p21(sdi1) expression in senescent cells after DNA damage, suggesting a mechanism of in vivo carcinogenesis in aged tissue without repair arrest
21399611	We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53
21399611	Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53
21399233	Resistance to discodermolide is mediated via resistance to accelerated cell senescence, and is associated with reduced expression of the mTORC1 substrate, 4E-BP1 and increased expression of p53 [1]
21399233	Although the association of p53 with senescence induction is well-characterized, senescence reversion in the presence of high expression of p53 has not been well-documented
21399233	Furthermore, studies addressing the role of mTOR signaling in regulating senescence have been limited and recent data implicate a novel, senescence-associated role for 4E-BP1 in crosstalk with the transcription factor p53
21391904	Pharmacological activation of p53 in cancer cells
21391904	Tumor suppressor p53 is a transcription factor that regulates a large number of genes and guards against genomic instability
21391904	Under multiple cellular stress conditions, p53 functions to block cell cycle progression transiently unless proper DNA repair occurs
21391904	During neoplastic progression, p53 is often mutated and fails to efficiently perform these functions
21391904	It has been observed that cancers carrying a wild-type p53 may also have interrupted downstream p53 regulatory signaling leading to disruption in p53 functions
21391904	Therefore, strategies to reactivate p53 provide an attractive approach for blocking tumor pathogenesis and its progression
21391904	A large number of small molecules capable of reactivating p53 have been developed and some are progressing through clinical trials for prospective human applications
21391904	For example, it is not certain if pharmacological activation of p53 will restore all of its multifaceted biological responses, assuming that the targeted cell is not killed following p53 activation
21391904	It remains to be demonstrated whether the distinct biological effects regulated by specific post-translationally modified p53 can effectively be restored by refolding mutant p53
21391904	Mutant p53 can be classified as a loss-of-function or gain-of-function protein depending on the type of mutation
21391904	It is also unclear whether reactivation of mutant p53 has similar consequences in cells carrying gain-of-function and loss-of-function p53 mutants
21391904	This review provides a description of various pharmacological approaches tested to activate p53 (both wild-type and mutant) and to assess the effects of activated p53 on neoplastic progression
21383005	Since melanomas often retain wild-type p53 function activating p21, our findings describe a novel mechanism whereby EZH2 activation during tumor progression represses p21, leading to suppression of cellular senescence and enhanced tumorigenicity
21364961	The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice
21364961	CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation
21363920	Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation
21363920	The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD
21363920	In addition, high levels of infiltrating leukocytes were associated with telomere shortening, senescence, and reduced p53 expression
21336312	Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction
21334322	The p53 transcription factor is activated by various types of cell stress or DNA damage and induces the expression of genes that control cell growth and inhibit tumor formation
21334322	Analysis of mice that express mutant forms of p53 suggest that inappropriate p53 activation can alter tissue homeostasis and life span, connecting p53 tumor suppressor functions with accelerated aging
21334322	However, other mouse models that display increased levels of wildtype p53 in various tissues fail to corroborate a link between p53 and aging phenotypes, possibly due to the retention of signaling pathways that negatively regulate p53 activity in these models
21334322	Deletion of Mdm2, the chief negative regulator of p53, induced an aging phenotype in the skin of mice, including thinning of the epidermis, reduced wound healing, and a progressive loss of fur
21334322	These results reveal that activation of endogenous p53 by ablation of Mdm2 can induce accelerated aging phenotypes in mice
21334198	Anticancer effects of the p53 activator nutlin-3 in Ewing's sarcoma cells
21334198	Mutation of p53 is rare in Ewing's sarcoma (ES), suggesting that targeting and activation of wild-type p53 may be an effective therapeutic strategy for ES
21334198	The recently developed small-molecule MDM2 inhibitor nutlin-3 restores wild-type p53 function, resulting in the inhibition of cancer cell growth and the induction of apoptosis
21334198	In the present study, we explored the responsiveness of ES cell lines with wild-type or mutated p53 to nutlin-3
21334198	We found that treatment with nutlin-3 increased p53 level and induced p53 target gene expression (MDM2, p21, PUMA) in ES cells with wild-type p53, but not in ES cells with mutated p53
21334198	Our findings suggest that the direct activation of p53 by nutlin-3 treatment may be a useful new therapeutic approach for patients with ES
21331045	CKIalpha ablation highlights a critical role for p53 in invasiveness control
21331045	The epithelial DNA damage response in mice is accompanied by substantial activation of p53, suggesting that the p53 pathway may counteract the pro-tumorigenic effects of Wnt hyperactivation
21331045	Notably, the transition from benign adenomas to invasive colorectal cancer in humans is typically linked to p53 inactivation, underscoring the importance of p53 as a safeguard against malignant progression; however, the mechanism of p53-mediated tumour suppression is unknown
21331045	Furthermore, in p53-deficient gut, loss of heterozygosity of the gene encoding CKIalpha caused a highly invasive carcinoma, indicating that CKIalpha functions as a tumour suppressor when p53 is inactivated
21331045	We identified a set of genes (the p53-suppressed invasiveness signature, PSIS) that is activated by the loss of both p53 and CKIalpha and which probably accounts for the brisk induction of invasiveness
21331045	Restraining tissue invasion through suppressing PSIS expression is thus a novel tumour-suppressor function of wild-type p53
21325273	VentX trans-activates p53 and p16ink4a to regulate cellular senescence
21319227	This senescence-like response was mediated by intracellular ROS generation, but was not attributed to p53 Ser15 phosphorylative activation and was uncoupled from the p21cip1 axis, which has been shown to mediate Pten loss-induced cellular senescence or oncogene-driven senescence
21317932	A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation
21317932	Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo
21317932	The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially
21317932	Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter
21317932	These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53
21286718	The effects of cetuximab or irinotecan as single agents or the combination on the expression of p53, p16, and EGFR signaling pathways were also studied
21286718	The combination could also inhibit the expression of Cyclin D1 and phosphorylated mTOR while had no impact on p53, p16, PTEN, and HIF-1alpha
21278790	Mechanistic dissection showed that alpha-catulin depletion strongly induced the DNA-damage response (DDR) in both cell lines, via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53
21276412	In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age
21267786	Colon cancer cell lines (Caco-2 and HCT116(-/-) p53) were used to assess YPEL3 gene expression after treatment with 5-azadeoxycytidine or trichostatin A
21266744	Uncapped or dysfunctional telomeres are an endogenous DNA damage that activates ATM kinase (ataxia telangiectasia mutated) and then p53 to induce cellular senescence or apoptosis
21245959	Cell counts were performed for 10 days, and features of senescence were analyzed using senescence-associated beta-galactosidase staining, the telomeric repeat amplification protocol for telomerase activity, Southern blot analysis for mean telomere length, flow cytometric analysis for cell-cycle arrest, and western blot for p53 and p21
21212468	Remarkably, overexpressed Zfra induces apoptosis via the mitochondrial pathway, which involves suppression of Bcl-2 and Bcl-xL expression (without causing cytochrome c release), counteracting the apoptotic function of tumor suppressor p53 and WWOX, and dissipation of mitochondrial membrane potential for ultimately leading to cell death
21212468	Control of cellular aging and apoptosis by Zfra, p53 and WWOX is discussed
21212465	DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence
21212465	Senescence occurs when p53 fails to inhibit mTOR
21212465	Low concentrations of DNA-damaging drugs induce p53 at levels that do not inhibit mTOR, thus causing senescence
21212465	This predicts that induction of p53 will not cause senescence in such quiescent cells
21212465	Serum starvation prevented induction of senescence, but not of p53, by etoposide
21212465	We conclude that induction of p53 does not activate the senescence program in quiescent cells
21212465	In cells with induced p53, re-activation of mTOR by serum stimulation causes senescence, as an equivalent of cellular growth
21205865	Here, we show that the mechanism by which PML induces a permanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcription factors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1alpha
21196260	While reports of other YPEL family members have surfaced our laboratory was the first to report that YPEL3 is induced by the p53 tumor suppressor
21190955	Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated beta-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1
21188535	Senescence related genes p16, p21 and p53 increased gradually in BM-MSC
21188535	However, p16 and p53 reduced and then increased but with the gradual increase of p21 in UC-MSC
21182935	Knockdown or inhibition of AR activity in primary cultured keratinocytes enhanced UVB-induced cellular senescence and increased the level of a cell-cycle regulatory protein, p53
21176396	Cell contact accelerates replicative senescence of human mesenchymal stem cells independent of telomere shortening and p53 activation: roles of Ras and oxidative stress
21176396	Moreover, cell cycle checkpoint regulator P53 expression was not affected by cell contact
21176396	Taken together, cell contact induced accelerated senescence of MSCs, which is telomere shortening and p53 independent
21173253	The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response
21173253	Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells
21173253	Furthermore, the stability of p53 was enhanced in AD32 cells
21159650	Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924
21124965	ING2 also functionally interacts with the tumor suppressor protein p53 to regulate cellular senescence, apoptosis and DNA damage response in vitro, and is thus expected to modulate carcinogenesis and aging
21124965	Their testes showed degeneration of seminiferous tubules, meiotic arrest before pachytene stage with incomplete meiotic recombination, induction of p53, and enhanced apoptosis
21124965	This phenotype was only partially abrogated by concomitant loss of p53 in the germline
21118958	Unlike transient foci, DNA-SCARS associate with PML nuclear bodies, lack the DNA repair proteins RPA and RAD51, lack single-stranded DNA and DNA synthesis and accumulate activated forms of the DDR mediators CHK2 and p53
21118958	DNA-SCARS form independently of p53, pRB and several other checkpoint and repair proteins but require p53 and pRb to trigger the senescence growth arrest
21116678	At the molecular level, age-related resistance to apoptosis involves (1) functional deficiency in p53 network, (2) increased activity in the NF-kappaB-IAP/JNK axis, and (3) changes in molecular chaperones, microRNAs, and epigenetic regulation
21110788	Tumor-suppressor protein p53 induces genes critical for implementing cellular senescence
21110788	However, the identities of p53 target genes and other regulators that achieve senescence under oxidative stress remain to be elucidated
21110788	Bach1-deficient MEFs bypassed the senescence state when the expression of a subset of p53 target genes, including p21, Pai1, Noxa, and Perp, was simultaneously reduced by using RNAi
21110788	These results suggest that oxidative stress-induced cellular senescence is registered by multiple p53 target genes, which arrest proliferation redundantly, in part by activating pRb
21110788	Our elucidations contrast with previous reports describing monopolistic regulations of senescence by single p53 target genes
21099361	Our data revealed that Nek6 expression is decreased both in both the replicative senescence of human normal fibroblasts and premature senescence induced by p53 expression in EJ human bladder cancer cells and H1299 human lung cancer cells
21099361	Mechanistic studies revealed that cell cycle arrest in the G1 and G2/M phases, as well as the reduction of cyclin B and cdc2 protein level upon p53 expression were significantly reduced by Nek6 overexpression
21099353	Although p53 and Rb pathways are activated in the absence of Akap12, senescence is dependent on Rb
21099244	The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAi- transfected stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G0-G1 phase with high expression of senescence-associated beta-galactosidase
21084274	Evidence indicates that the induction of senescence occurs as a result of reactive oxygen species elevation followed by low-level activation of the caspase cascade, insufficient to induce apoptosis, but sufficient to lead to minor DNA damage and increases in p53, p21, IL-6 and 8 proteins
21084274	By overexpression of a dominant-negative p53 protein, we show that ABT-737-induced cellular senescence is p53-dependent
21078269	Expressions of p53 and RB were unchanged after TLBZD treatment
21057505	At the end of cellular replicative lifespan, uncapped telomeres lose this protective mechanism and DNA-damage signalling pathways are triggered that activate p53 and thereby induce replicative senescence
21057505	This study reveals that p53, a downstream effector of telomere-initiated damage signalling, also functions upstream of the shelterin complex
21051933	Weak p53 permits senescence during cell cycle arrest
21051933	While arresting cell cycle, high levels of p53 can inhibit mTOR (in some cell lines), thus causing reversible quiescence instead of senescence
21051933	Nutlin-3a-induced p53 inhibited mTOR and thus caused quiescence in WI-38 cells
21051933	Super-induction of p53 by either nutlin-3a or high concentrations of DOX (high-DOX) prevented low-DOX-induced senescence, converting it into quiescence
21051933	This explains why in order to cause senescence, DNA damaging drugs must be used at low concentrations, which arrest cell cycle but do not induce p53 at levels sufficient to suppress mTOR
21051933	We conclude that low p53 levels during prolonged cell cycle arrest tend to cause senescence, whereas high levels of p53 tend to cause either quiescence or cell death
21047732	OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene
21047732	We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors
20978349	Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53
20978349	Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice
20978349	In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas
20974249	CHIP-dependent p53 regulation occurs specifically during cellular senescence
20974249	However, other E3 ligases have been identified, such as the chaperone-associated ligase CHIP, although their precise function regarding p53 degradation remains elusive
20974249	In this study, we explore the role of CHIP in regulating p53 in senescence
20974249	We demonstrate that in senescent human fibroblasts, CHIP is up-regulated concomitant with a significant down-regulation of p53
20974249	Notably, CHIP overexpression in young cells, to levels similar to those recorded during senescence, leads to p53 degradation to below its basal levels
20974249	In addition, whereas CHIP silencing has no effect on p53 stability in young cells, a considerable p53 accumulation occurs in their senescent counterparts
20974249	Finally, we have observed an attenuation of the CHIP-associated molecular folding-refolding machinery during senescence, and supportively, inhibition of Hsp90 activity leads to rapid p53 degradation only in senescent cells
20974249	Taking these results together, we conclude that CHIP-dependent p53 regulation occurs specifically during senescence
20974153	The p53 feedback loop can induce cellular senescence, cell cycle arrest and apoptosis in response to various stresses, including DNA damage, hypoxia and nutrient deprivation
20974153	Using a stochastic model of the negative feedback circuit involving p53 and its inhibitor Mdm2, we present the different oscillatory dynamics at the single-cell and population-cell levels as described in the experiments, and the resonant nature of the oscillations is captured
20969773	P16INK4a was downregulated, p53 was low expressed and Bax/Bcl-2 ratio was reversed
20969773	The expression of p53 and p16INK4a in BME65Cs was altered in the pattern of down-regulation but not "loss", suggesting that this spontaneous immortalization is possibly initiated by other mechanism rather than gene mutation of p53 or p16INK4a
20950777	The onset and maintenance of senescence are regulated by two tumor suppressors, p53 and retinoblastoma proteins
20950777	The expression of p53 and retinoblastoma proteins is regulated by two distinct proteins, p16(Ink4a) and Arf, respectively, which are encoded by cdkn2a
20948989	Certain miRNAs have been shown to function as integral components of the p53 and/or retinoblastoma (Rb) regulatory networks
20940041	Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging
20940041	The stress-activated signaling pathways, p53 and NF-kappaB, have a major role in the regulation of cellular senescence and organismal aging
20940041	WIP1 (wildtype p53-induced phosphatase 1) and MIF (macrophage migration inhibitory factor) are signaling molecules which link together the p53 and NF-kappaB pathways via positive and negative feedback loops
20940041	It seems that the efficiency of the p53 signaling pathway declines during aging whereas that of NF-kappaB is clearly enhanced
20940041	Moreover, p53 is an important trigger of cellular senescence while NF-kappaB signaling seems to be involved in the induction of the senescence-associated secretory phenotype (SASP)
20940041	MIF is a pro-inflammatory cytokine which inhibits the function of p53 signaling whereas it is linked to NF-kappaB signaling via a positive feedback loop
20940041	An increased level of MIF can support inflammatory responses via enhancing NF-kappaB signaling and repressing the function of p53
20940041	Several observations indicate that the activity of WIP1 decreases during the aging process, this being probably attributable to the decline in p53 function
20940041	We will review the findings linking WIP1 and MIF to specific signaling responses of p53 and NF-kappaB and discuss their role in the regulation of cellular senescence and organismal aging
20937593	Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation
20935678	Negative regulation of the tumor suppressor p53 gene by microRNAs
20935678	The tumor suppressor p53, encoded by the TP53 gene, is recognized as the guardian of the human genome because it regulates many downstream genes to exercise its function in cell cycle and cell death
20935678	Recent studies have revealed that several microRNAs (miRNAs) are important components of the p53 tumor suppressor network with miR-125b and miR-504 directly targeting TP53
20935678	In this study, we use a screening method to identify that two miRNAs (miR-25 and miR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels and reduce the expression of genes that are transcriptionally activated by p53
20935678	Inhibition of either miR-25 or miR-30d expression increases endogenous p53 expression and elevates cellular apoptosis in several cell lines, including one from multiple myeloma that has little TP53 mutations
20935678	Thus, beyond miR-125b and miR-504, the human TP53 gene is negatively regulated by two more miRNAs: miR-25 and miR-30d
20890302	Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19(Arf), Trp53 and p21(Cdkn1a)
20890302	In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence
20876940	TP53 and MTOR crosstalk to regulate cellular senescence
20876940	The full spectrum of activities of the tumor suppressor p53 (TP53) has not been completely elucidated yet
20876940	Recently, it was demonstrated that TP53 communicates with the metabolic regulator mechanistic target of rapamycin (MTOR) to determine whether stressed cells undergo cell death, reversible quiescence or irreversible senescence, thereby adding yet another level of complexity to the signaling network that emanate from TP53
20858887	The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein
20841375	2 induced growth arrest without additional cellular stress in cancer cells lacking functional p53, p16, and/or Rb
20819672	The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts
20819672	Furthermore, increases in apoptotic cell death and p53 expression were observed
20819672	The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration
20818171	Other gene products like p53, SUV39H1 or TGFbeta promoted senescence, which together with apoptosis contributed to tumor suppression
20724842	Cellular senescence is an irreversible state of terminal growth arrest that requires functional p53
20724842	Acting to block tumor formation, induction of senescence has also been demonstrated to contribute to tumor clearance via the immune system following p53 reactivation
20724842	The Hdm2-antagonist, Nutlin-3a, has been shown to reactivate p53 and induce a quiescent state in various cancer cell lines, similar to the G(1) arrest observed upon RNAi targeting of Hdm2 in MCF7 breast cancer
20720180	Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate
20720180	Indoxyl sulfate inhibited serum-induced cell proliferation and promoted the activation of senescence-associated beta-galactosidase, a marker of cellular senescence, and the expression of alpha-smooth muscle actin (alpha-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation
20720180	Pifithrin-alpha, p-nitro, a p53 inhibitor, blocked these effects
20720180	Indoxyl sulfate evoked reactive oxygen species (ROS), and the antioxidant N-acetylcysteine inhibited indoxyl sulfate-induced p53 expression and phosphorylation, as well as indoxyl sulfate-induced alpha-SMA expression
20720180	Taken together, these findings indicate that indoxyl sulfate induces the expression and phosphorylation of p53 though ROS production, thus inhibiting cell proliferation and promoting cellular senescence and renal fibrosis
20705054	Senescence growth arrest is known to be controlled by p53 phosphorylation/p21(WAF1/Cip1) induction or p16(INK4a)/retinoblastoma protein (pRB) activation
20705054	SM22alpha overexpression in HepG2 cells elevated p16(INK4a) followed by pRB activation, but did not activate the p53/p21(WAF1/Cip1) pathway
20703098	Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence
20703098	This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa
20703098	In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice
20703098	Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa
20694676	Post-translational modification of p53 by ubiquitin
20694676	Post-translational modification of p53 by ubiquitin resides in the center of a fine-tuned regulatory network that activates the tumor suppressor in response to genotoxic stress
20694676	Inhibition of p53 ubiquitination by DNA damage not only prevents p53 from degradation but also promotes its nuclear accumulation leading to transactivation of a number of downstream genes that are essential for the control of cell cycle progression, cell survival, and cellular senescence
20694676	Therefore, there are growing interests in studying p53 ubiquitination under physiological/pathological conditions
20694676	We describe herein a cell-based method and an in vitro reconstituted assay that are convenient, reproducible, and adaptable for various experimental conditions for detection of p53 ubiquitination
20694676	Wide application of these methods in studying mechanisms underlying regulation of p53 ubiquitination shall assist us in better understanding of the function of the tumor suppressor
20679489	In support of this concept, senescence following VHL loss depends on p53 activity, which decreases under the less stressful conditions of mild hypoxia
20660729	Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence
20660729	In response to replicative aging, DNA damage, and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells by inducing senescence or apoptosis
20660729	Both regulate p53 transcriptional activity toward a subset of its target genes required for replicative and oncogenic stress senescence induction, and BRD7 physically interacts with p53
20660729	BRD7 is a deletion target in human cancer, suggesting that loss of BRD7 may provide an additional mechanism to antagonize p53 function in cancer cells
20659896	The p53 regulatory network is critically involved in preventing the initiation of cancer
20659896	Active p53 initiates transcriptional and transcription-independent programs that result in cell cycle arrest, cellular senescence, or apoptosis
20659896	Subsequently, when stress-induced post-translational modifications start to decline, HDM2 becomes effective in targeting p53 for degradation, thus attenuating the p53 response
20647331	Coincident with these DNA damage markers, the level of p53 protein and genes transcriptionally activated by p53, such as p21, TP53INP1, and DDIT4, increased
20647331	The importance of the p53 pathway to PIM1-driven cellular senescence was further shown by the observation that expression of dominant-negative p53 or shRNA targeting p21 blocked the PIM1-induced changes in the DNA damage response and increases in SA-beta-Gal activity
20624405	AIMS: the aims of the study are to investigate the additive effect of exogenous short-carbon chain phospholipids, C(2)-ceramide, on an anti-cancer drug paclitaxel (PTX)-induced senescence of human non-small cell lung cancer (NSCLC) cells deficient in functional p53 and p16, and to examine whether mitogen-activated protein kinase (MAPK) plays a role in ceramide-sensitized senescence of NSCLC cells
20624405	Importantly, neither p53, p21(waf1/cip1) nor p16(ink4) was shown to be involved in C(2)-ceramide-sensitized proliferative inhibition and senescence of H1299 cells by PTX in our study
20624280	BACKGROUND: The p53 signalling pathway has hundreds of inputs and outputs
20624280	Signals from all these inputs are channeled through a single node, the transcription factor p53
20624280	Further, our model provides a framework for predicting the differences in p53 response to different stresses and single nucleotide polymorphisms
20622898	Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis
20622898	One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response
20622898	It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions
20622898	The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest
20622898	On the other hand, p53 itself induces G1 arrest and has no effect on the G2
20622898	Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses
20622898	This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains
20622894	The heat-shock transcription factor HSF1 was recently shown to have a key role in the development of tumors associated with activation of Ras or inactivation of p53
20605919	We demonstrate that telomerase extends HGPS cellular lifespan by decreasing progerin-induced DNA-damage signaling and activation of p53 and Rb pathways that otherwise mediate the onset of premature senescence
20603525	Another "Janus paradox" of p53: induction of cell senescence versus quiescence
20569234	Similar to p53 and p21 depletion, BTG2 depletion in human fibroblasts leads to an extension of cellular lifespan, and ectopic BTG2 induces senescence independently of p53
20536843	The process involves activation of the p53 and Rb tumor suppressor pathways and mitochondrial dysfunction
20535839	Many studies showed that exogenous telomeric repeats could activate p53 protein
20534396	It has long been known that loss of a key tumour suppressor gene, such as p53 or pRB, is necessary but not sufficient for spontaneous cellular immortalisation
20501696	MORC3 (microrchidia family CW-type zinc-finger 3), also known as NXP2, which consists of GHL-ATPase, a CW-type zinc-finger and coiled-coil domains, is localized in PML NBs, where it recruits and activates p53 to induce cellular senescence
20500145	Targeting the p53 pathway of apoptosis
20500145	The tumor suppressor protein, p53 is regarded as a key player in tumor suppression, as it promotes growth arrest, apoptosis and cellular senescence, while also blocking angiogenesis
20500145	The plethora of mechanisms underlying the p53 efficient death response involves transcriptional activation or repression of target genes, as well as the recently identified microRNAs, and transcription-independent functions
20500145	Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis or atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role
20500145	In this regard, therapeutic strategies aimed at reactivation of p53 in tumors emerge as a promising approach for the treatment of cancer patients, as well as chemical inhibitors of p53 that may prove effective in suppressing disorders associated with widespread p53 activation
20500145	In addition, we will discuss controversies arising from the double-edge sword of targeting p53 in disease
20500145	Finally, ursodeoxycholic acid (UDCA), an endogenous bile acid used to treat cholestatic liver diseases, was recently described as a fine modulator of the complex control of p53 by Mdm-2
20498645	Pharmacological reactivation of mutant p53: from protein structure to the cancer patient
20498645	The p53 tumor suppressor pathway blocks tumor development by triggering apoptosis or cellular senescence in response to oncogenic stress
20498645	A large fraction of human tumors carry p53 mutations that disrupt DNA binding of p53 and transcriptional regulation of target genes
20498645	Reconstitution of wild-type p53 in vivo triggers rapid elimination of tumors
20498645	Therefore, pharmacological reactivation of mutant p53 is a promising strategy for novel cancer therapy
20498645	Several approaches for identification of small molecules that target mutant p53 have been applied, including rational design and screening of chemical libraries
20498645	The compound PhiKan083 binds with high affinity to a crevice created by the Y220C mutation in p53 and stabilizes the mutant protein
20498645	The compound PRIMA-1 (p53 reactivation and induction of massive apoptosis) restores wild-type conformation to mutant p53 by binding to the core and induces apoptosis in human tumor cells
20485437	Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential
20485437	Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development
20473858	At high concentrations, Dox activates p53 leading to apoptosis without enhancing p21 expression
20473858	Here, we report that the DNA methyltransferase (DNMT) DNMT3a was upregulated by Dox especially at concentrations that induced apoptosis in HCT116 colorectal cancer cells, and this process was regulated by p53
20463968	A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence
20463968	Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria [1]
20463968	TP53 can independently partition with endogenous nuclear and mitochondrial proteins consistent with the ability of p53 to enact senescence
20463968	In order to address the role of p53 in navigating cellular senescence through the mitochondria, we identified SirT3 to rescue EJ/p53 cells from induced p53-mediated growth arrest
20463968	Human SirT3 function appears coupled with p53 early during the initiation of p53 expression in the mitochondria by biochemical and cellular localization analysis
20463968	Our evidence suggests that SirT3 partially abrogates p53 activity to enact growth arrest and senescence
20463968	These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity
20457898	Paradoxical suppression of cellular senescence by p53
20457898	The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology)
20457898	Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53
20457898	In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest
20457898	Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence
20457898	We found that in p21-arrested cells, p53 converted senescence into quiescence
20457898	Suppression of senescence by p53 required its transactivation function
20457898	Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway
20457898	We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53
20457898	Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence
20457353	Depletion of securin induces senescence after irradiation and enhances radiosensitivity in human cancer cells regardless of functional p53 expression
20457353	Depletion of securin impairs DNA repair after irradiation, increasing DNA damage and promoting senescence in the residual surviving cells regardless of functional p53 expression
20457152	In irradiation-resistant p53-mutated lymphoma cell-lines (Namalwa and WI-L2-NS) but not sensitive p53 wild-type counterparts (TK6), low background expression of OCT4 and NANOG was up-regulated by ionising radiation with protein accumulation evident in ETC as detected by OCT4/DNA flow cytometry and immunofluorescence (IF)
20446924	ChIP (chromatin immunoprecipitation) analysis demonstrates co-ordinated binding of two transcription factors to the promoter of the p53 tumour-suppressor gene
20446924	It was previously reported that binding of two transcription factors, C/EBPbeta and RBP-Jkappa, to a regulatory site on the p53 promoter regulates its activity, in vitro, in a cell cycle-dependent manner
20446924	Our reports, here and previously published, show that repression of p53 by RBP-Jkappa and activation of p53 by C/EBPbeta through differential binding of these two factors indicates a type of co-operative regulation in p53 expression
20446924	Here, we demonstrate through the use of chromatin immunoprecipitation (ChIP) assays that the co-ordinated binding of these two factors to the p53 promoter occurs in vivo and serves to regulate p53's activity during the cell cycle
20431990	The p53 gene is a key tumor suppressor and its deletion or mutation allows cancerous growth
20431990	The switching on of p53 also causes changes in fatty acid metabolism, especially down-regulation of both fatty acid synthase and stearoyl-CoA (delta-9) desaturase
20428768	The results thus suggest that low doses of radiation suppress doxorubicin-induced replicative senescence through the inhibition of p38-dependent phosphorylation of p53 and by activation of ERK1/2, without genomic damage
20424117	Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors
20424117	We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to the enrichment of an EMT-competent cellular subpopulation among telomerase-immortalized human esophageal epithelial cells during malignant transformation
20424117	Enrichment of EMT-competent cells was more evident in the presence of p53 mutation, which diminished EGFR-induced senescence
20424117	Thus, senescence checkpoint functions activated by EGFR and p53 may be evaded through the induction of ZEB, thereby allowing the expansion of an EMT-competent unique cellular subpopulation, providing novel mechanistic insights into the role of ZEB in esophageal carcinogenesis
20422055	METHODOLOGY/PRINCIPAL FINDINGS: Livers of five children aged three years or less undergoing liver transplantation due to tyrosinemia (n = 1), biliary atresia (n = 2), or fulminant hepatitis (n = 2) were analyzed for senescence associated beta-galactosidase (SA-betagal) activity and p16INK4a, p21cip1 and p53
20422055	Staining for p53 had a similar distribution to that observed for SA-betagal
20388804	Although both processes require a functional p53 signaling pathway, relevant downstream p53 targets have been difficult to identify
20388804	In microarray studies in which p53 was reactivated in MCF7 cells, we discovered that Yippee-like-3 (YPEL3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-5, is a p53-regulated gene
20388804	YPEL3 expression induced by DNA damage leads to p53 recruitment to a cis-acting DNA response element located near the human YPEL3 promoter
20388804	Through the use of RNAi and H-ras induction of cellular senescence, we show that YPEL3 activates cellular senescence downstream of p53
20385362	Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence
20378935	Senescence escape and immortalisation have been intensively studied in murine embryonic fibroblasts as a model system, and are known to occur when the p53/ARF tumour suppressor pathway is disrupted
20378935	We showed recently that murine fibroblasts with a humanised p53 gene (Hupki cells, from a human p53 knock-in mouse model) first senesce, and then become immortalised in the same way as their homologues with normal murine p53
20378935	Here we consider various routes to p53/ARF disruption in senescence bypass, and dysfunction of other tumour suppressor networks that may contribute to release from tenacious cell cycle arrest in senescent cultures
20374652	Expression of the master cell cycle regulators p53 and p21 and growth factors HGF and VEGF also declined significantly at 26 months
20372780	The response of Ishikawa cells expressing wt p53 was different compared to other cell lines
20331441	Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status
20331441	Unexpectedly, the accumulation of damaged cells was found to occur independent from the DNA damage response modulator p53, and from an intact immune system, as their levels were similar in wild-type and Rag2(-/-) gammaC(-/-) mice, the latter being deficient in T, B, and NK cells
20214620	Important mechanisms ensuring the stop of genomically altered cells to proliferate are the activation of ATM, p53 and the DNA damage response (DDR)
20201066	The ability of stem cells to propagate indefinitely is believed to occur via the fine modulation of pathways commonly involved in cellular senescence, including the telomerase, the p53, and the mitochondrial/oxidative stress pathways
20201066	Accordingly, iPSCs exhibit alterations of the senescence-related telomerase and p53 signaling pathways
20197621	Further, we found that PICS is associated with enhanced p53 translation
20197380	These include increased staining of senescence-associated beta-galactosidase, increased nuclear and cell body size, vacuolated cellular morphology, upregulation/stabilization of p53, p21, and hypophosphorylated pRb
20183804	The p53 tumor suppressor is a sequence-specific transcription factor and acts as a central hub sensing various stress signals and activating an array of target genes to induce cell cycle arrest, apoptosis, and senescence
20183804	Recent reports showed that restoration of p53 induces premature senescence and tumor regression in mice with hepatocarcinomas or sarcomas
20183804	In this review, we will discuss how p53 regulates senescence and future studies about p53 family members in senescence
20174572	However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype
20174572	We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53
20174572	Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors
20174572	Finally, our work shows that levels of activated AKT are not essential in the induction of benign or premalignant tumors, or in the cooperation of AKT with other tumorigenic signal such as mutant p53, once AKT pathway is activated, the relative level of activity seems not to determine the phenotype
20164124	Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53
20164124	This induction is associated with higher levels of p16(INK4A) and phosphorylated p53
20164124	Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC
20160511	The p53 response element and transcriptional repression
20160511	The canonical p53 response element (p53RE), which contains two repeats of a decamer motif "RRRCWWGYYY" separated by a spacer of 0 to 13 base-pairs, has been characterized as the regulatory region on the target genes that p53 binds for transcriptional activation
20160511	It was thought that p53 generally represses genes that lack this canonical p53RE, presumably through the sequestration of basal transcriptional machinery components or transcription activators
20160511	Taken together, there appears to be multiple modes of gene repression by p53 with some being mediated through direct binding of p53 to DNA
20160501	This inhibitory effect was not dependent on the status of p53 and p21 although GDP366 potently increased p53 and p21 levels
20160010	This premature senescence is dependent on a tumor suppressor, p53, but not on p16(INK4a)-Rb; the depletion of CENP-A in p53-deficient cells results in aberrant mitosis with chromosome missegregation
20157557	Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3
20157557	The p53 tumor suppressor plays a key role in induction and maintenance of cellular senescence but p53-regulated response to stress in senescent cells is poorly understood
20157557	Here, we use the small-molecule MDM2 antagonist, nutlin-3a, to selectively activate p53 and probe functionality of the p53 pathway in senescent human fibroblasts, WI-38
20157557	Our experiments revealed overall reduction in nutlin-induced transcriptional activity of nine p53 target genes and four p53-regulated microRNAs, indicating that not only p53 protein levels but also its ability to activate transcription are altered during senescence
20157557	Addition of nutlin restored doxorubicin-induced p53 protein and transcriptional activity in senescent cells to the levels in early passage cells but only partially restored its apoptotic activity, suggesting that changes in both upstream and downstream p53 signaling during senescence are responsible for attenuated response to genotoxic stress
20157556	Awakening p53 in senescent cells using nutlin-3
20153804	Pttg deletion abrogates tumor development by activating p53/p21-dependent senescence pathways
20118236	Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53/ARF pathway disruption in spontaneous escape from senescence
20118236	To investigate senescence and genetic alterations in the p53 pathway that lead to senescence bypass in culture, we compared the behavior of MEFs from wild-type mice with MEFs from Hupki mice, which harbor a humanized p53 gene
20118236	Surprisingly, in spontaneously immortalized cell lines from both wild-type and Hupki MEFs, the predominant type of p53 mutation was a G to C transversion, rather than the G to T substitutions expected from the raised oxygen levels characteristic of standard culture conditions
20089117	Overexpression of the mutant protein in primary fibroblasts is associated with telomere-based cellular senescence, multinucleated cells and the activation of the DNA damage response genes ATM, Chk2 and p53
20085733	Vitamin C can alleviate cell senescence by p53 repression and may accelerate reprogramming by synergizing with epigenetic regulators
20060114	OBJECTIVE: The expression of p53 has been associated with DNA damage, cell senescence, proliferation and apoptosis in human atherosclerotic plaques
20060114	However, it is largely unknown whether p53 expression is related to the stability and clinical manifestations of atherosclerotic plaques in humans
20060114	In the present study, we examined whether p53 expression is related to clinical symptoms and plaque integrity in patients with carotid atherosclerosis (n=62)
20060114	We also investigated p53 expression and its relation to apoptosis and apoptosis-related cathepsin L and ferritin in the carotid lesions
20060114	METHODS AND RESULTS: We found that smooth muscle cells often had nuclear p53 in the shoulder region of carotid lesions while CD68-positive macrophages, which had both nuclear and cytoplasmic p53, frequently appeared in the surrounding areas of necrotic cores or plaque cap regions
20060114	Quantitative image analysis of immunohistochemistry showed that p53 expression was significantly increased in plaques with necrotic core formation or cap rupture and lesions from patients with transient ischemic attacks (TIAs)
20060114	The levels of p53 expression was significantly increased in more severe stenosed lesions but decreased with prolonged time between symptom onset and carotid endarterectomy
20060114	Furthermore, p53 expression was significantly correlated with the expression of ferritin, lysosomal cathepsin L, and apoptosis
20060114	CONCLUSION: The increased p53 expression, particularly macrophage p53 levels, is associated with the enlargement of necrotic cores, plaque rupture and clinical manifestations of carotid plaques
20060114	Concomitant increases of lysosomal cathepsin, ferritin, and p53 levels may promote the apoptosis and atheroma progression in patients with carotid atherosclerosis
20057963	The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer
22073357	These effects could be explained by induction of damage to genomic DNA by ROS that accelerates cell senescence through p53 activation
20032638	The pathways mediating OIS are complex and incompletely elucidated but, the proliferative arrest involves activation of both the RB and p53 pathways
20016203	The basal and stimulated (by TNF-alpha) levels of NFkappaB were augmented in senescent cells in electrophoretic mobility shift assays in association with increased oxidative stress, increased p53 protein stability, and activated apoptotic pathways
20016203	CONCLUSIONS: After multiple passaging in vitro, porcine coronary endothelial cells exhibited dysfunction and senescence associated with reduced proliferative capacity, increased oxidative stress, and activation of the NFkappaB and p53 signaling pathways
20007091	These effects could be explained by induction of damage to genomic DNA by ROS that accelerates cell senescence through p53 activation
20005456	Furthermore, we found that irradiation with C-ions induced cellular senescence in a human glioma cell line lacking functional p53
19955394	Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways
19954840	The present work shows that the decrease of the hydrophobic property of poly (ethylene-co-vinyl alcohol) (EVAL) from 44 mole% to 27 mole% ethylene could induce characteristic senescence-associated phenotypic changes such as larger cell shape, re-organized actin cytoskeleton, lower proliferation capacity, higher levels of senescence-associated beta-galactosidase (SA beta-gal) activity, and upregulation of the cell-cycle inhibitor p53 and its transcriptional target p21 in the cultured human diploid fibroblasts (HDFs)
19951988	WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway
19951988	Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21(WAF1) signaling pathway
19951988	By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence
19948976	Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53
21994573	The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21(Cip1) and p16(INK4a)/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage
19916829	Apart from playing a crucial role in tumor suppression, the p53 signaling pathway also has important functions in the regulation of metabolism, organ development, and cellular senescence
19916829	A recent important advance in the p53 field is the uncovering of presence of various p53 isoforms in vivo
19916829	Although full-length p53 is well known to promote cell apoptosis and cell cycle arrest, the roles of p53 isoforms in these processes are still elusive
19916829	In this review, we summarized the recent studies on the p53 isoform Delta113p53 regarding its regulation and function in zebrafish and discussed the potential use of Tg(Delta113p53:gfp) transgenic fish for identification of novel factors involved in the p53 pathway and for screening of new compounds for cancer therapy
19906512	Telomere homolog oligonucleotides (T-oligos) induce adaptive DNA damage responses including increased DNA repair capacity and these effects are mediated, at least in part, through p53
19906512	METHODS: Normal human fibroblasts as well as R2F fibroblasts expressing wild type or dominant negative p53 were treated with an 11-base T-oligo, a complementary control oligo or diluents alone and then examined by western blot analysis, immunofluorescence microscopy and various biochemical assays
19906512	RESULTS: We now report that T-oligo increases the level of the antioxidant enzymes superoxide dismutase 1 and 2 and protects cells from oxidative damage; and that telomere-based gammaH2AX (DNA damage) foci that form in response to T-oligos contain phosphorylated ATM and Chk2, proteins known to activate p53 and to mediate cell cycle arrest in response to oxidative stress
19855935	A senescent marker appeared after staining for senescence-associated beta-galactosidase activity in wild-type HCT116 cells treated with CKII inhibitor or CKIIalpha siRNA, but this response was almost abolished in p53- or p21(Cip1/WAF1)-null cells
19855935	Increased cellular levels of p53 and p21(Cip1/WAF1) protein occurred with the inhibition of CKII
19855935	CKII inhibition upregulated p53 and p21(Cip1/WAF1) expression at post-transcriptional level and transcription level, respectively
19855165	In the same cell lines, the Mdm2 inhibitor nutlin-3a induced p53 but, unexpectedly, caused quiescence (reversible arrest) with a small cell morphology
19833883	Previously, we reported that DNA double-strand breaks (DSBs) resulting from nonhomologous end-joining (NHEJ) deficiency induce apoptosis and, when combined with p53 deficiency, progressed rapidly into lymphomagenesis in mice
19833883	We also profiled DNA damage and p53 and p21 expression in the pancreas
19833883	We observed an accumulation of DNA damage, accompanied with increased levels of p53 and p21, a significant decrease in beta-cell proliferation, and cellular senescence in the mutant pancreatic islets
19833096	These effects were associated with decreased 8-iso-prostaglandin F(2alpha) and peroxynitrite formation, enhanced protein expression of NAD(+)-dependent class III histone deacetylase sirtuin (SIRT) 1, and downregulated protein expression of histone senescence factor p53
19820694	A TrxR1 mutant lacking the CBM, which fails to localize to caveolae and bind to caveolin 1, is constitutively active and inhibits oxidative-stress-mediated activation of the p53/p21(Waf1/Cip1) pathway and induction of premature senescence
19820694	Thus, caveolin 1 links free radicals to activation of the p53/p21(Waf1/Cip1) pathway and induction of cellular senescence by acting as an endogenous inhibitor of TrxR1
19802007	Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence
19799355	We assessed the ability of sodium butyrate (NaB), a histone deacetylase inhibitor (HDACi), to reactivate the cellular senescence program in either E1A + cHa-Ras-transformed rat embryo fibroblasts with wild-type p53 (ERas(WT)) and in the isogenic cell line where p53 was inactivated due to expression of the potent genetic suppressor element GSE56 (ERas(GSE56))
19799355	NaB treatment increased p53 transcriptional activity and induced an irreversible G1/S cell cycle arrest in ERas(WT), but not in ERas(GSE56) cells
19799355	By the transient transfections method using reporter luciferase (p53-LUC) constructions, it was shown that p53-LUC activity as a marker of p53 transactivation function did not increase after X-rays exposure of transformants ERas(GSE56)
19799355	Thus, our results suggest that induction of p53 transcription activity could be the key determinant of HDACi-induced cell cycle arrest and senescence in transformed cells and provide an additional evidence of SA-beta-Gal invalidity as a sufficient senescence marker
19769983	NFAT-siRNA treatment attenuated Ang-II-increased SA-beta-gal activity and p53 and p21 expression
19769983	In contrast, VSMC prepared from ATRAP transgenic (ATRAP-Tg) mice exhibited attenuation of Ang-II-induced SA-beta-gal activity, oxidative stress, NFAT transcriptional activity, and expression of p53 and p21
19767771	As a transcription factor, the critical tumor suppressor, p53, directly regulates the transcription of hundreds of genes, leading to cell-cycle arrest, apoptosis, cellular senescence and differentiation
19767771	Although it has been assumed that p53 transcription activity is critical for tumor suppression, this assumption has been increasingly contested by recent findings of transcription-independent roles of p53 in apoptosis as well as findings that none of the mutant mice lacking important p53 transcription targets are cancer prone
19767771	On the basis of previous findings that p53 transcription activity is abolished in p53(QS) (Leu25Trp26 to Gln25Ser26) knock-in mouse cells after DNA damage, to determine the importance of transcription activity of p53 in tumor suppression, we generated knock-in mice that can conditionally express p53(QS) protein in a Cre-dependent manner
19767771	Therefore, p53 transcription activity induced by DNA damage is required for tumor suppression
19767771	Together with the findings that the disruption of various p53-dependent functions individually fails to promote cancer, our findings indicate that various transcription-dependent functions of p53 must collaborate to efficiently suppress tumorigenesis
19737973	Pharmacologic p53 activation blocks cell cycle progression but fails to induce senescence in epithelial cancer cells
19737973	The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system
19737973	Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways
19737973	However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling
19737973	We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells
19737973	Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control
19737973	Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro
19723919	Cox proportional hazard models computed hazard ratio (HR) for death, adjusted for potential confounders, including p53, cyclin D1, KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI)
19718037	A crucial role for adipose tissue p53 in the regulation of insulin resistance
19718037	This response is controlled by tumor suppressor proteins such as p53 and pRb
19718037	Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders
19718037	We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines
19718037	Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease
19718037	Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance
19718037	Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967)
19716796	Using mouse embryonic fibroblasts with constitutively increased DNA damage due to the absence of the full-length form of the tumor suppressor Brca1 (Brca1(Delta 11/Delta 11)), we show that deletion of p53 binding protein 1 (53BP1) selectivity abrogates senescence and cell death stimulated by reduced Brca1 activity
19710698	Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells
19710698	It has been reported that the induction of cellular senescence through p53 activation is an effective strategy in tumor regression
19710698	Unfortunately, however, tumors including adult T-cell leukemia/lymphoma (ATL) have disadvantages such as p53 mutations and a lack of p16(INK4a) and/or p14(ARF)
19710698	Eight cell lines, including six ATL-related cell lines, had wild-type p53 and Nutlin-3a-activated p53, and the cell lines underwent apoptosis or cell-cycle arrest, whereas eight cell lines with mutated p53 were resistant
19710698	Furthermore, knockdown of Tp53-induced glycolysis and apoptosis regulator (TIGAR), a novel target gene of p53, by small interfering RNA(siRNA) indicated its important role in the induction of cellular senescence
19710698	As many patients with ATL carry wild-type p53, our study suggests that p53 activation by Nutlin-3a is a promising strategy in ATL
19701195	We show that the human p53 isoforms Delta133p53 and p53beta function in an endogenous regulatory mechanism for p53-mediated replicative senescence
19701195	The siRNA (short interfering RNA)-mediated knockdown of endogenous Delta133p53 induced cellular senescence, which was attributed to the regulation of p21(WAF1) and other p53 transcriptional target genes
19701195	In overexpression experiments, whereas p53beta cooperated with full-length p53 to accelerate cellular senescence, Delta133p53 repressed miR-34a expression and extended the cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence
19701195	The senescence-associated signature of p53 isoform expression (that is, elevated p53beta and reduced Delta133p53) was observed in vivo in colon adenomas with senescent phenotypes
19696787	Although members of the miR-34 family are known to be transcriptionally regulated by p53, we find that miR-34a is regulated independently of p53 during oncogene-induced senescence
19696787	Hence, in addition to its integration in the p53 pathway, we show that alternative cancer-related pathways regulate miR-34a, emphasising its significance as a tumour suppressor
19690330	One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults
19690330	Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response
19690330	In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19(Arf)
19690330	However, in contrast to that in the prostate epithelium, p19(Arf) deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance
19690330	Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway
19648966	In contrast, p53- or p21-negative cells treated with DNA-damaging agents failed to accumulate Rb2/p130 and to enter senescence
19616052	We found that simulated microgravity induced partial G1 phase arrest, upregulated senescence-associated beta-galactosidase (SA-beta-gal) activity, and activated both p53 and p16 protein pathways linked to cell senescence
19597334	In addition, Ku80 and p53 show a genetic interaction to suppress pro-B cell lymphoma and medulloblastoma
19591297	While the major cause of cellular senescence and aging is oxidative stress, little is known about how the p53 activity is regulated under such conditions
19591297	These findings provide completely novel insights into how the activity of p53 is regulated under oxidative stress
19591297	Since p53 is the critical tumor suppressor with huge clinical implications, the newly identified mechanism should open new research fields
19580491	The cellular response to chemoradiotherapy was investigated in cells of the HCT116 (wild-type TP53) and HT29 (mutated TP53) human colorectal cancer cell lines to better understand how the chemotherapeutic agent 5-fluorouracil (5-FU) acts as a radiosensitizer in vitro and how it contributes to the well-documented greater efficacy of chemoradiotherapy compared to radiotherapy (or chemotherapy) alone
19580491	The largest G(2)/M arrests and strongest correlation of senescence with non-clonogenicity were seen in radiotherapy- and chemoradiotherapy-treated HCT116 cell cultures, suggesting that functional TP53 could play a role in maintaining/inducing these cellular phenotypes
19562738	Tumour suppression by p53: the importance of apoptosis and cellular senescence
19562738	Importantly, p53 loss of function is required for tumour maintenance
19540815	OUTCOME MEASURES: We examined cell senescence markers (senescence-associated beta-galactosidase [SA-beta-gal], telomere length, telomerase activity, p53, p21, pRB, and p16) and the hydrogen peroxide (H(2)O(2)) content as a marker for an oxidative stress in the human NP specimens
19540815	For the mechanism involved in the senescence of NP chondrocytes, expressions of p53, p21, pRB, and p16 in these cells were assessed with immunohistochemistry and Western blotting
19540815	Immunohistochemistry showed that the senescent NP chondrocytes in all the specimens expressed p53, p21, and pRB, but a few NP chondrocytes in only two specimens expressed p16
19540815	Western blotting showed that the expressions of p53, p21, and pRB displayed a corresponding pattern, that is, a strong p53 expression led to strong p21 and pRB expressions and vice versa
19528227	The increase in mitochondrial mass and ROS in response to oncogenic ras depended on intact p53 and Rb tumor suppression pathways
19523975	The Pro/Pro genotype of the p53 codon 72 polymorphism modulates PAI-1 plasma levels in ageing
19523975	Recently, PAI-1 has been also identified in vitro as a critical downstream target of p53
19523975	TP53, the p53 gene, has a common functional polymorphism at codon 72 which influences the capability to modulate both apoptosis and cell senescence
19523975	In the attempt to demonstrate an in vivo role of p53 in the relationship between PAI-1 and age, we studied PAI-1 on 570 healthy subjects (aged from 18 to 92yrs
19523975	This is the first demonstration of an in vivo role of TP53 polymorphism in PAI-1 regulation, supporting the hypothesis that the effects of this polymorphism are age-dependent
19501586	Expression of endogenous levels of mutant K-Ras in differentiated acinar cells resulted in moderately elevated Ras activity and in sparse murine pancreatic intraepithelial neoplasias (mPanINs) that did not spontaneously advance to PDAC unless the tumor suppressor p53 was simultaneously deleted
19492297	This change is related to the p53 activity that negatively regulates APE1/Ref-1
19486941	Adaptive responses and loss of checkpoint proteins such as p53 and p16(INK4a) allow tumor cells to tolerate constitutive mitogenic signaling and enhanced production of ROS, leading to altered redox status in many fully transformed cells
19448667	The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells
19448667	The tumor suppressor p53 preserves genome integrity by inducing transcription of genes controlling growth arrest or apoptosis
19448667	The observation that tumor cell lines harboring wild-type p53 specifically maintain expression of BRG1 and that BRG1 complexes with p53 prompted us to examine the role of BRG1 in regulation of p53
19442113	ING proteins are putative tumor suppressor proteins functionally linked to the p53 pathway and to chromatin regulation
19442113	The currently available data support an important role of ING proteins as regulators of senescence, in connection with the p53 pathway and chromatin organization
19434633	These results indicate that AG2034 activates p53 and AMPK mediating the induction of signaling pathways leading to senescence
19433493	It binds to and inhibits p53 transcriptional activity
19432898	In addition, apoptosis was also induced in LoVo and HCT116 cells that harbored wild-type p53 and the reactive oxygen species (ROS) level was higher than in senescent cells
19432898	Finally, the induction of apoptosis was inhibited by using siRNA to downregulate p53
19427898	These changes are accompanied by increased intracellular ROS, accumulation of DNA damage, and induction of p53 and p21 proteins
19421407	Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53
19407340	However, down-regulation of p53, a target of lithium in EC, dampens both basal and lithium-induced MMP-1 expression, which further links MMP-1 up-regulation with the establishment of cell senescence
19396980	Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging
19396980	The tumor suppressors p16(INK4a) and p53 have been implicated as contributors to age-associated stem cell decline
19396980	Key functions of p53 are the induction of cell cycle arrest, senescence, or apoptosis in response to DNA damage
19396980	Here, we examine senescence, apoptosis, and DNA damage responses in a mouse accelerated aging model that exhibits increased p53 activity, the p53(+/m) mouse
19396980	Aged tissues of p53(+/m) mice display higher percentages of senescent cells (as determined by senescence-associated beta-galactosidase staining and p16(INK4a) and p21 accumulation) compared to aged tissues from p53(+/+) mice
19396980	Surprisingly, despite having enhanced p53 activity, p53(+/m) lymphoid tissues exhibit reduced apoptotic activity in response to ionizing radiation compared to p53(+/+) tissues
19396980	Ionizing radiation treatment of p53(+/m) tissues also induces higher and prolonged levels of senescence markers p16(INK4a) and p21, suggesting that in p53(+/m) tissues the p53 stress response is enhanced and is shifted away from apoptosis toward senescence
19381346	Our results also indicate that the p16(INK4a) signaling pathway may play a key role in the early stages of senescence in CECs while the p53/p21(WAF1/CIP1) signaling pathway may exert its principle effect in the late stages of senescence in CECs
19338757	Using p53-/- MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21(Cip1) accumulation
19318349	Expression of p21(Sdi1) downstream of p53 is essential for induction of cellular senescence, although cancer cell senescence can also occur in the p53 null condition
19295915	Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses
19295915	Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC) of telomerase-deficient mice with dysfunctional telomeres
19295915	In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro
19293188	This phenotype is accompanied by hypophosphorylated retinoblastoma protein (Rb) and accumulation of p21, which depends on functional p53
19286634	SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells
19286634	METHODS AND RESULTS: Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation
19286634	Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction
19273079	Senescence is a tumor suppressor mechanism triggered by oncogenic stimuli and characterized by a permanent cell cycle arrest mediated by tumor suppressors such as p53, Rb and PML
19273079	The mechanism of PML-induction during senescence is complex and includes increased PML gene transcription by p53 or transcription factors of the interferon/Jak/Stat pathway
19273079	In turn, PML engages both p53 and Rb, although the precise molecular processes are unknown
19273079	PML interacts with the DNA-binding domain of p53 facilitating p53 modifications
19264704	Induction of cellular senescence by secretory phospholipase A2 in human dermal fibroblasts through an ROS-mediated p53 pathway
19264704	In this study, we found that sPLA(2) treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated beta-galactosidase activity, changes in cell morphology, and upregulation of p53/p21 protein levels
19264704	These results suggest that sPLA(2) has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging
19235838	When FoxM1 in gastric cancer cells was knocked-down, impaired clonogenicity and cellular senescence occurred independently of p53 and p16 status
19235838	Taken together, the FoxM1 gene is aberrantly activated in gastric cancer and its inhibition triggers p53- and p16-independent senescence of cancer cells by regulating the expression of p27(kip1) and other targets
19224462	Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors
19224462	The p53 tumor suppressor gene is the most frequently mutated gene in human cancer; this gene is mutated in up to 50% of human tumors
19224462	Polymorphisms of p53 have been suggested to be associated with genetically determined susceptibility in various types of cancer
19224462	In the present study, we examined the TP53 Arg72Pro and Pro47Ser polymorphisms using PCR-RFLP and the pattern of methylation of the p53 gene by methylation-specific PCR in 90 extra-axial brain tumor samples
19224462	Patients who had the allele Pro of the TP53 Arg72Pro polymorphism had an increased risk of tumor development (odds ratio, OR = 3
19224462	We suggest that TP53 Pro47Ser and Arg72Pro polymorphisms and DNA hypermethylation are involved in susceptibility for developing extra-axial brain tumors
19221490	MiR-34, SIRT1 and p53: the feedback loop
19221490	The TP53 is one of the most commonly mutated genes in human cancers, and its gene product p53 activates transcription of a set of miRNA including the miR-34 family of miRNA
19221490	SIRT1 also regulates p53 dependent apoptosis through deacetylating and stabilizing p53
19221490	We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity
19221490	Based on this observation, we propose a positive feedback loop, in which p53 induces expression of miR-34a which suppresses SIRT1, increasing p53 activity
19197340	The M-type receptor PLA2R regulates senescence through the p53 pathway
19197340	Taken together, our study identifies PLA2R as a potential new tumour suppressor gene crucial in the induction of cellular senescence through the activation of the p53 pathway
19169823	Cellular senescence is a potent anti-cancer mechanism controlled by tumor suppressor genes, particularly p53 and pRb, which is characterized by the irreversible loss of proliferation
19164294	The Cspg2(Delta3/Delta3) fibroblasts showed a substantial increase of ERK1/2 phosphorylation and expression of senescence markers p53, p21, and p16
19150958	Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation
19141477	CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation
19141477	In CPEB knockdown cells, p53 mRNA has an abnormally short poly(A) tail and a reduced translational efficiency, resulting in an approximately 50% decrease in p53 protein levels
19141477	An shRNA-directed reduction in p53 protein by about 50% also results in extended cellular life span, reduced respiration and ROS, and increased glycolysis
19141477	Together, these results suggest that CPEB controls senescence and bioenergetics in human cells at least in part by modulating p53 mRNA polyadenylation-induced translation
19118192	This senescent phenotype recapitulated several salient features of replicative senescence, notably the presence of senescence-associated beta-galactosidase (SA beta-gal) activity, apparently irreparable genomic DNA breaks, and elevation of p21(Cip1), p53, and p16(INK4A) tumor suppressor protein levels
20232599	BMI-1 interferes with the central cellular tumor suppressor pathways linked to retinoblastoma protein (Rb) and p53
20232599	While the roles of the pathways associated with Rb and p53 in cancer are broadly established, further elucidation thereof in stem cells might have implications in cancer research, stem cell biology and regenerative medicine
19099650	Morphology, senescence-associated beta-galactosidase (SA-beta-gal) staining and cell cycle analysis were used to evaluate the changes in BMMSCs at cellular level while real-time RT-PCR was used to detect the alterations in senescence related gene expression including p16INK4a, p21Cip1/Waf1, p53 and TGF-beta1
19079133	We showed that mouse embryonic fibroblasts (MEFs) from ku80(-/-) mice senesced rapidly with elevated levels of p53 and p21
19079133	Deletion of p21 delayed the early senescence phenotype in ku80(-/-) MEFs, despite an otherwise intact response of p53
19070423	Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a)
19053174	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor
19053174	Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein
19053174	Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs
19053174	Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment
19048622	We have previously shown that complete responses to high doses epirubicin-cyclophosphamide were observed only in human tumors bearing a TP53 mutation
19048622	Three xenografted human breast tumors, 2 of them with a TP53 mutation and one of them without, were studied for their immediate response to this drug association
19048622	The TP53 wild-type tumor showed a strong early induction of senescence-like phenotype with overexpression of SA-beta-gal and p21(CIP1)
19048622	In contrast both TP53 mutated tumors showed no sign of cell cycle arrest or senescence
19048622	Conversely, abnormal mitoses strongly increased, only in TP53 mutated tumors
19048622	Thus, in these in vivo models, epirubicin-cyclophosphamide treatment induces senescence-like features in TP53 wild-type tumor, likely accounting for cell cycle arrest and subsequent resistance to treatment
19048622	Conversely in TP53 mutated tumors, chemotherapy induces mitotic catastrophe and tumor death, accounting for complete response to this association exclusively in patients with TP53 mutated tumors
19034270	Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs
19034270	Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53
19034270	These miRNAs are repressed by p53 in an E2F1-mediated manner
19034270	Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit
19015633	HPV16 E6 oncoprotein binds and often targets for degradation numerous cell proteins, including the tumor suppressor p53 and several PDZ domain proteins
19015633	The E6 F47R mutant is defective for polyubiquitination and subsequent degradation of p53
19015633	When expressed in HPV-positive cervical cancer cells, E6 F47R acts as a dominant negative mutant by counteracting the p53 degradation activity of endogenous E6 and restoring high p53 protein levels
19015633	F47R-senescent HeLa cells exhibit a sustained expression of p53, hMDM2 and p21(CIP) proteins and a reduced expression of endogenous HPV18 E6 protein
19015633	Finally, small interfering RNAs directed against p53 counteract the effect of E6 F47R expression, indicating that E6 F47R-induced cellular senescence is strongly dependent on p53 signaling pathway
19011671	EC exhibited higher expression levels of markers of oxidative stress (lipid peroxydation level and caveolin-1 mRNA), inflammation (angiopoietin-like 2 mRNA), hypoxia (vascular endothelial growth factor (VEGF)-A mRNA), and cell damage (p53 mRNA)
19001376	The tumor suppressor protein, p53, is central to the pathways that monitor the stress, DNA damage repair, cell cycle, aging, and cancer
19001376	Highly complex p53 networks involving its upstream sensors and regulators, downstream effectors and regulatory feedback loops have been identified
18982914	In addition, aging due to both mechanisms (DNA damage and telomere shortening) is strongly dependent on p53 status
18974396	Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53
18974396	Here, we reported that functional activation of p53 in normal young HDFs and p53-null Saos2 cell line resulted in transcriptional activation of the IFI16 gene
18974396	We identified a potential p53 DNA-binding site (indicated as IFI16-p53-BS) in the 5'-regulatory region of the IFI16 gene
18974396	Importantly, p53 bound to IFI16-p53-BS in a sequence-specific manner in gel-mobility shift assays
18974396	Furthermore, p53 associated with the 5'-regulatory region of the IFI16 gene in chromatin immunoprecipitation assays
18974396	Interestingly, p53 associated with the regulatory region of the IFI16 gene only on treatment of cells with DNA-damaging agents or in the old, but not in the young, HDFs
18974396	Importantly, our promoter-reporter assays, which were coupled with site-directed mutagenesis of IFI16-p53-BS, showed that p53 activates transcription of the IFI16 gene in HDFs through the p53 DNA-binding site
18974396	Together, our observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence
18949386	The senescence-like phenotype (SLP) induced by p53, which showed a morphological change and an irreversible cell cycle arrest, was not observed in vitamin C-treated EJ cells
18948382	Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS
18948382	However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53
18948382	Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence
18948382	Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia
18852884	Senescent fibroblasts exhibited enhanced expression of phosphorylated and acetylated p53, and cyclin-dependent kinase inhibitor, p21
18848576	The senescence-regulating effect of selective COX-2 inhibitors had no correlation with cellular reactive oxygen species levels, NF-kappaB activities or protein levels of p53 and p21
18847333	EtOH also transactivated the luciferase activity of the p21 promoter region independent of additional exogenous ERalpha, activated p21 and p53, and stimulated senescence-associated beta-galactosidase activity in rat stromal osteoblasts
18847333	We conclude that inhibitory cross-talk between EtOH and E2 in osteoblasts on ERs, p53/p21, and cell senescence provides a pathophysiologic mechanism underlying bone loss and the protective effects of estrogens in alcohol-exposed females
18845560	Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells
18845560	To determine if the p53-mediated pathway was involved in hepaCAM-induced senescence, we used the small-interfering RNA system to knock down endogenous p53 expression
18845560	Together, the results suggest that the expression of hepaCAM in MCF7 cells not only inhibits cell growth but also induces cellular senescence through the p53/21 pathway
18845559	Coexpression of cyclin D1, but not a dominant-negative p53, rescued proliferation in the Cdx2-expressing cells
18843795	We show that wild-type p16(INK4a) promotes rapid cell cycle arrest that leads to a senescence programme characterized by the appearance of chromatin foci, activation of acidic beta-galactosidase activity, p53 independence and Rb dependence
18838863	While some of these factors have been previously shown to possess different pro-tumorigenic activities, we recently demonstrated that the secretion of CXCR2-binding chemokines (such as IL-8 or GROalpha) by senescent cells contribute to reinforce senescence via activation of the p53 pathway
18836456	Knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb- and p53 pathway-dependent manner
18830775	Research has demonstrated that the HPV-expressed E6 and E7 proteins function concomitantly to disrupt the p53 and retinoblastoma (Rb) tumor suppressor genes, regulators of the cell-cycle checkpoints at the first gap (G(1)) phase
18829542	In premature senescence, this novel secretory phenotype was dependent on the activation of p53
18813784	Mutation of the p53 gene is a common event in human cancer
18813784	Interestingly, p53 mutation is uncommon in nasopharyngeal carcinoma (NPC)
18813784	The DeltaNp63 has been postulated to have a dominant-negative effect on the function of the p53 gene and may play a role in the pathogenesis of nasopharyngeal carcinoma
18800172	Characterization of the p53 response to oncogene-induced senescence
18800172	BACKGROUND: P53 activation can trigger various outcomes, among them reversible growth arrest or cellular senescence
18800172	Furthermore, the relative contribution of p53 to Ras-induced senescence is also matter of controversy
18800172	METHODOLOGY/PRINCIPAL FINDINGS: This study compared situations in which different signals drove senescence with increasing levels of p53 activation
18800172	The study revealed that the levels of p53 activation do not determine the outcome of the response
18800172	Furthermore, while p53-dependent transcription decreases after 24 hrs in the presence of active p53, senescence continues
18800172	CONCLUSIONS: The levels of p53 activation do not determine the outcome of the response
18800172	Rather, p53 activity seems to act as a necessary but not sufficient condition for senescence to arise
18783169	The p53 network is perhaps the most important pathway involved in preventing the initiation of cancer, p53 levels and activity are upregulated in response to various stresses including DNA damage, hypoxia, and oncogene activation
18783169	Active p53 initiates different transcriptional programs that result in cell cycle arrest, cellular senescence or apoptosis
18783169	Previous studies showed that the level of p53 increased dramatically after exposure to damaging radiation, then declined in a series of damped oscillations
18783169	Recent quantitative studies examined p53 responses in individual living cells, using time-lapse fluorescent microscopy and showed that-on an individual cell level-the oscillations are not damped
18783169	Instead, one cell may have only one pulse of p53, while its neighbor may show several repeated pulses
18783169	As the amount of irradiation increased, the percentage of cells showing a high number of p53 pulses also increased
18783169	These observations opened new questions regarding the mechanism and function of p53 oscillatory dynamics
18783169	In this chapter I will review the different models that have been suggested for p53 oscillations, including proposed reasons for variation between cells, and will discuss potential functions for oscillatory dynamics in the p53 signaling pathway and in stress responses in general
18729810	Our data demonstrated that both LPA and ACI inhibit the catalytic activity of AMPKalpha and p53 by differentially regulating phosphorylation of AMPKalpha, causing increased senescent cell proliferation
18711403	It has long been known that loss of a key tumor suppressor gene, such as p53, is necessary, but not sufficient, for spontaneous cellular immortalization
18711403	We identified universal genes regulating senescence/immortalization and found that the key regulator genes represented six pathways: the cell cycle pRB/p53, cytoskeletal, interferon-related, insulin growth factor-related, MAP kinase and oxidative stress pathway
18706112	BACKGROUND: In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage
18706112	We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop
18706112	Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage
18706112	The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53
18706112	The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation
18706112	The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop
18706112	Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer
18701096	Western blot confirmed down-regulation of phosphorylated retinoblastoma protein (pRB) and up-regulation of p53 in IGFBP-rP1-transfectants as compared with control cells
18701096	Our results uncovered a novel molecular mechanism involving the altered expression of pRB and p53 for tumor suppressor gene IGFBP-rP1 in colorectal cancer
18672169	Up-regulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wild-type, but not in TERT(-/-) mice
18668528	In addition, though not yet proven experimentally, overcoming cellular senescence of fibroblasts by inactivating Rb and p53 pathways and up-regulating telomerase activity may also be required
18628455	RESULTS: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence
18604170	Senescence in most cells is regulated through some combination of activities within the RB and p53 pathways
18592462	CONCLUSION: BMI1 is a potent repressor of retinoblastoma and p53 pathways, and hence, elucidating its role in tumorigenesis is very important
18587721	Studies support a central role for Rb protein in controlling this process via signaling from the p53 and p16 pathways
18577387	Oscillations and bistability in the stochastic model of p53 regulation
18577387	The p53 regulatory pathway controls cell responses, which include cell cycle arrest, DNA repair, apoptosis and cellular senescence
18577387	We propose a stochastic model of p53 regulation, which is based on two feedback loops: the negative, coupling p53 with its immediate downregulator Mdm2, and the positive, which involves PTEN, PIP3 and Akt
18577387	The positive feedback destroys the negative coupling between Mdm2 and p53 by sequestering most of Mdm2 in cytoplasm, so it may no longer prime the nuclear p53 for degradation
18577387	However, when DNA repair is inefficient, the active p53 rises to a high level and triggers transcription of proapoptotic genes
18577387	The stochasticity of p53 regulation, introduced at the levels of gene expression, DNA damage and repair, leads to high heterogeneity of cell responses and causes cell population split after irradiation into subpopulations of apoptotic and surviving cells, with fraction of apoptotic cells growing with the irradiation dose
18513492	Most functions are dependent on the tumor suppressor p53
18513492	Here, we show that p33ING2 contains a transferable silencing function, which is independent of p53
20411135	METHODS: We examined cell senescence markers [senescence-associated beta-galactosidase (SA-beta-gal), telomere length, telomerase activity, p53, p21, pRB and p16] and the hydrogen peroxide (H(2)O(2)) content in human NP specimens
20411135	Immunohistochemistry showed that senescent NP chondrocytes in all specimens expressed p53, p21, and pRB, while a few NP chondrocytes in only two specimens expressed p16
20411135	Furthermore, the telomere-based p53, p21, pRB pathway, rather than the stress-based p16, pRB pathway, plays a more important role in the senescence of NP chondrocytes in in vivo conditions
18505922	By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53
18451178	Moreover, persistent loss of IGF-IR expression in dorsal and ventral lobes induced p53-regulated apoptosis and cellular senescence rescue programs, predicting that titration of IGF-IR signaling might facilitate growth of tumors with compromised p53 activity
18451178	Therefore, we crossed the mice carrying the prostate-specific IGF-IR knockout alleles into the transgenic adenocarcinoma of the mouse prostate model that is driven, in part, by T antigen-mediated functional inactivation of p53
18451178	Consistent with our prediction, prostate epithelial-specific deletion of IGF-IR accelerated the emergence of aggressive prostate cancer when p53 activity was compromised
18451145	Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence
18451145	Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis
18451145	Although p53 is mutated or deleted in approximately 50% of all cancers, p53 is still functionally active in the other 50%
18451145	Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53
18451145	Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development
18451145	Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites
18451145	In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation
18451145	Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway
18448098	In the setting of an intact p53 pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism
18448098	However, rare cells that stochastically lose p53 function emerge from this sea of genomic instability and progress towards cancer
18440596	The cellular DNA damage response (DDR) entails the activation of ATM, ATR and/or DNA PK protein kinases that causes modifications of proteins including Chk1, Chk2 and 53BP1, aggregation of DDR proteins into foci, and activation of p53
18425358	FACS analysis showed that UVB-stressed HSFs were blocked mostly in the G1 phase of the cell cycle, and replicative senescence, and protein expression of p53, p21(WAF-1) and p16(INK-4a) increased significantly
18413811	New molecular cancer treatment strategies aim to reconstitute wild-type p53 (WTp53) function in mutant p53 (MTp53)-expressing tumors as a means of resensitizing cells to chemotherapy or radiotherapy
18413811	Herein, we describe an isogenic, temperature-sensitive p53 model (p53(A138V)) in p53-null human H1299 lung cancer cells in which WTp53 can be selectively coexpressed with a temperature-sensitive MTp53 allele (A138V) during initial DNA damage and subsequent DNA repair
18413811	Cells expressing MTp53 alone or coexpressing induced WTp53 and MTp53 were tested for p53 transcription, G(1) and G(2) cell cycle checkpoints, apoptosis, and long-term clonogenic survival following DNA damage
18413811	This should be considered when using p53 as a prognostic factor and therapeutic target
18378907	Deletion of the p19(ARF), p53, or p21(WAF1) tumor suppressors but not p16(INK4a) prevented senescence and permitted tumorigenesis
18378907	These tumors expressed high levels of p19(Arf), p53, and p21(Waf1), demonstrating that Id1 acts to make cells refractory to p21(Waf1)-dependent cell cycle arrest
18372918	To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53
18372918	We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells
18372918	Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model
18362329	This coincides with up-regulation of p53 and dysregulation of NF-kappaB
18314458	Plaques were analyzed for ubiquitin levels, proteasome 20S activity, p16 and p53, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay)
18262222	The increase in BAX tracked the level of P53, a transcriptional regulator of BAX
18241911	Indices of aging including oxidative damage, ROS levels and p21 and p53 all increased suggesting a loss of MSC fitness with age
18231726	Several genes important for chromatin remodeling such as the tumor suppressors p53 and retinoblastoma (Rb) affect cellular senescence by mediating changes in chromatin structure and gene expression
18216268	Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence
18216268	The contribution of transcriptional activation to the p53 effector functions critical for tumor suppression, apoptosis and cellular senescence, remains unclear because of p53's ability to regulate diverse cellular processes in a transactivation-independent manner
18216268	Dissociating the importance of transactivation from other p53 functions, including regulating transcriptional repression, DNA replication, homologous recombination, centrosome duplication, and mitochondrial function, has been difficult because of overlapping motifs for these functions in the amino terminus
18216268	To determine the relative contribution of these activities and transactivation to p53 function, we generated knockin mice expressing a p53 mutant lacking domains involved in these transactivation-independent functions, while remaining competent for transactivation through fusion to the Herpes Simplex Virus VP16 transactivation domain
18216268	This chimeric mutant, termed p53(VP16), robustly activates the transcription of a range of p53 targets involved in both apoptosis and senescence
18216268	Intriguingly, despite being transactivation-competent, this chimeric protein shows selectivity in p53 effector function in mouse fibroblasts, with a capacity to trigger senescence but not apoptosis under a variety of conditions
18216268	Our study highlights the central role of p53 transactivation for senescence while suggesting that transactivation is insufficient for apoptosis, and provides insight into the mechanisms by which p53 serves as a tumor suppressor
18215413	Paradoxically, the introduction of telomerase is proposed as a method to combat ageing via cell therapy and a possible method to regenerate tissue, while telomerase inhibition and telomere shortening is suggested as a possible therapy to defeat cancers with intact p53
18206261	Moreover, only TGF-beta rescued p53 expression, Rb response pathway, and induced cellular senescence
18203716	Mammalian Sir2 (SIRT1) has also been found to regulate premature cellular senescence induced by the tumor suppressors PML and p53
18202802	The tumor suppressor protein p53 restricts proliferation in response to DNA damage or the deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence
18202802	Consequently, p53 mutations increase cell proliferation and survival and in some settings promote genomic instability and resistance to certain anti-cancer drugs
18178582	Quantitative proteomics analysis of the effects of ionizing radiation in wild type and p53 K317R knock-in mouse thymocytes
18178582	The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair
18178582	Following exposure to a variety of stresses, p53 becomes post-translationally modified with concomitant increases in activity and stability
18178582	To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53(K317R) knock-in mice was studied at the global level
18178582	We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53
18178582	Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53(K317R) thymocytes as well as a decrease in tumor necrosis factor alpha signaling
18178582	These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between the DNA damage response and other signaling pathways
18089797	Our data revealed mechanistic and functional differences between v1 and v5: (a) v1, but not v5, functions through the maintenance of telomeric 3' overhangs; (b) p53 is indispensable to v5 knockdown-induced senescence; and (c) v5 functions at only a fraction of telomeres to prevent DNA damage signaling
18076574	Our results demonstrated that ARF or p53 deletion cancels the senescence in Mel18-null MEFs, and the fact that p16(INK4a) is up-regulated in double-null MEFs suggests that the ARF/p53 pathway plays a central role in stress-induced senescence
18068755	Herein it is shown that the induction of UVB-induced premature senescence is associated with a transient increase of protein abundance and DNA-binding activity of p53
18068755	Silencing p53 expression with small interfering RNA (siRNA) affected the basal level of SA beta-gal and proliferative potential, but did not prevent UVB-induced increase of SA beta-gal and decrease of DNA synthesis
18068755	We used a senescence-specific low-density DNA array and p53 siRNA to study the mRNA abundance of 240 senescence-related genes and identified several potential p53-dependent genes differentially expressed after the repeated exposures to UVB
18059157	The p53 protein responds to irradiation-induced DNA damage by removing critically damaged cells from the proliferative pool
18059157	The finding that senescence is a primary mechanism of tumor regression indicates that p53 activators or downstream effectors may prove effective in radiosensitizing some carcinoma of the prostate
18056431	The guardian's little helper: microRNAs in the p53 tumor suppressor network
18056431	Several recent studies have implicated the miR-34 family of miRNAs in the p53 tumor suppressor network
18031612	The expressions of p21 and p53 was upregulated with PAB treatment, and cyclin B1 was upregulated and transported from the cytoplasm to nuclei, and sustained stable levels
18031568	We also found that promyelocytic leukemia protein and acetylated p53, key proteins involved in stress-induced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes
18025081	In this regard, a cDNA microarray assay was performed to identify p53 targets involved in senescence
18025081	Taken together, our data provided strong evidence that DEC1 is one of the effectors downstream of p53 to promote premature senescence
17991883	Global oxidative DNA damage triggers SIPS and telomere DNA damage accelerates replicative senescence, both mediated via p53
17991883	SIPS was associated with increased p53 expression but was not dependent on telomere attrition because overexpression of human telomerase did not prevent Ang II-induced SIPS
17968325	Inactivation, at least partial, of these genes confers resistance to both p53- and p16INK4a-induced proliferation arrest
17968325	Furthermore, such inactivation inhibits p53 but not E2F1 transcriptional activity and impairs DNA-damage-induced transcription of p21
17967869	Shuttling imbalance of MLF1 results in p53 instability and increases susceptibility to oncogenic transformation
17967869	Here we show that MLF1 is a cytoplasmic-nuclear-shuttling protein and that its nucleolar localization on fusing with NPM prevents the full induction of p53 by both genotoxic and oncogenic cellular stress
17964297	To understand whether integrin beta4 is involved in vascular endothelial cell (VEC) senescence, we examined integrin beta4 level changes, as well as P53 and reactive oxygen species (ROS) levels and alterations of phosphatidylcholine-specific phospholipase C (PC-PLC) activity before and after knocking-down integrin beta4 by small interfering RNA
17964297	We found integrin beta4, P53 and ROS levels increased significantly, while Ca(2+)-independent PC-PLC activity obviously decreased during VEC senescence
17964297	On the other hand, integrin beta4 down-regulation attenuated the senescence phenotype and reversed Ca(2+)-independent PC-PLC activity, and P53 and ROS levels
17964297	The data suggested that integrin beta4 might mediate VEC senescence through depressing Ca(2+)-independent PC-PLC and elevating the levels of P53 and ROS
17942417	Two faces of p53: aging and tumor suppression
17942417	The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells
17942417	In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence)
17942417	Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging
17942417	Here, we discuss the role of p53 as a key regulator of the DNA damage responses, and discuss how p53 integrates the outcome of the DNA damage response to optimally balance tumor suppression and longevity
17934643	TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population
17934643	TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes
17934643	Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases
17934643	TP53 codon 72 (TP53:72) polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study
17916362	Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53
17916362	Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered
17916362	These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression
17913706	We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response
17911410	The unusual presence of wild-type P53 in TGCTs is explained by specific expression of a cluster of micro-RNAs (miRNAs), that is, hsa-miR 371-373, also expressed in ES cells, which prevents P53-driven cellular senescence upon oncogenic stress
17902269	OBJECTIVE: To investigate the course of tubular cell senescence and expressions of p53, p21, and Rb during the late phase of ischemia/reperfusion (IRI) in the kidney, and assess the effects of the p53-Rb pathway on tubular cell senescence
17902269	Histological changes at the tubular level, progress of cell senescence, and the expression of Rb, p21, and/or p53 proteins in tubular cells were studied at different moments in time after IRI
17902269	RESULTS: Chronic tubulointerstitial fibrosis was much more severe and widely distributed in IRI kidneys of p53 (+/+) mice in later stages than in earlier stages
17902269	In contrast, in contralateral kidneys of p53 (+/+) mice and in both kidneys of p53 (-/-) mice, almost no senescent cells were observed at 1 and 3 months after IRI, and only a few senescent cells were detected in IRI kidneys of p53 (-/-) mice at 6 months
17902269	In mice of both genotypes, cell senescence was correlated with the expression levels of p53, p21, and Rb proteins
17898049	Human papillomavirus E6 proteins mediate resistance to interferon-induced growth arrest through inhibition of p53 acetylation
17898049	For instance, E7 acts to increase p53 levels while E6 accelerates its rate of turnover through the binding of the cellular ubiquitin ligase E6AP
17898049	Treatment of E7-expressing cells with interferon ultimately resulted in cellular senescence through a process that is dependent upon acetylation of p53 by p300/CBP at lysine 382
17898049	Cells expressing mutant forms of E6 that are unable to bind p300/CBP or bind p53 failed to block acetylation of p53 at lysine 382 and were sensitive to growth arrest by interferon
17898049	In contrast, mutant forms of E6 that are unable to bind E6AP remain resistant to the effects of interferon, demonstrating that the absolute levels of p53 are not the major determinants of this activity
17898049	Finally, p53 acetylation at lysine 382 was found not to be an essential determinant of other types of senescence such as that induced by overexpression of Ras in human fibroblasts
17873905	CDC20, a potential cancer therapeutic target, is negatively regulated by p53
17873905	The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence
17873905	A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed
17873905	To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of whole-genome expression profiles, one for cells in which wild-type p53 was exogenously introduced and the other for a large number of clinical cancer tissues
17873905	Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53
17873905	CDC20 expression was suppressed by genotoxic stresses in p53- and p21-dependent manners through CDE-CHR elements in the CDC20 promoter
17873905	Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal fibroblast cells
17873905	Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer
17846709	Cyclin-dependent kinase inhibitors, including p53 and p21, were also upregulated in TETA-treated MCF-7 cells
17804819	Premature senescence induced by IGFBP-5 up-regulation in young cells was rescued by knockdown of p53, but not by knockdown of p16
17767195	Dysfunctional telomeres activate p53 to initiate cellular senescence or apoptosis to suppress tumorigenesis
17767195	However, in the absence of p53, telomere dysfunction is an important mechanism to generate chromosomal instability commonly found in human carcinomas
17721438	Importantly, knockdown of either p53 or p21Cip1, but not p16(INK4a) or Rb, allows cells to bypass premature senescence that is induced by BS69 knockdown
17721438	Furthermore, we show that BS69 forms complexes with both p53 and p400, and that BS69 associates with the p21Cip1 promoter through p53
17700066	DNA damage response (DDR) emerges as a biological tumorigenesis barrier in early stages of cancer development, and a selective pressure that favors outgrowth of malignant clones with defects in the genome maintenance machinery, such as mutations of p53 and other DDR components
17700066	The higher load of DNA damage may also contribute to cancer predisposition in families with inherited heterozygous defects in the DDR barrier, such as in ATM, BRCA1, BRCA2, p53 and other genes
17671427	Here we review evidence indicating that oncogene induced senescence (OIS) involves activation of p53 via the DNA damage response (DDR)
17671205	Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53
17671205	Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest
17671205	Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53
17664422	Similarly, only after lymphomas were repaired for p53 expression did MYC inactivation induce robust senescence and sustained tumor regression
17662641	We show that bleomycin-treated A549 cells exhibit: senescence-like cell morphology; a senescence-associated increase in SA-beta-galactosidase activity; cell cycle arrest; and upregulation of p53 and p21
17662641	Interestingly, senescence-associated cell cycle arrest via p53 and p21 and SA-beta-galactosidase activity is reduced in young A549 cells when short hairpin RNA specific for caveolin-1 was applied before bleomycin-treatment
17662641	Our results support the hypothesis that downregulation of caveolin-1 expression affects bleomycin-induced cell cycle arrest and subsequent cellular senescence that is driven by p53 and p21
17643369	Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA
17643075	Recently we reported a surveillance mechanism linking loss of Bub1 to activation of the p53 pathway, specifically premature cell senescence in normal human fibroblasts
17635417	Down-regulation of IGFBP3 rescued the growth arrest induced by p53 overexpression in young HUVECs
17634581	Thereby, p53 seems to be essential for the senescence response
17595514	H2O2 accelerates cellular senescence by accumulation of acetylated p53 via decrease in the function of SIRT1 by NAD+ depletion
17595514	It has been reported that p53 acetylation, which promotes cellular senescence, can be regulated by the NAD(+)-dependent deacetylase SIRT1, the human homolog of yeast Sir2, a protein that modulates lifespan
17595514	To clarify the role of SIRT1 in cellular senescence induced by oxidative stress, we treated normal human diploid fibroblast TIG-3 cells with H(2)O(2) and examined DNA cleavage, depletion of intracellular NAD(+), expression of p21, SIRT1, and acetylated p53, cell cycle arrest, and senescence-associated beta-galactosidase (SA-beta-gal) activity
17595514	The amount of acetylated p53 was increased in TIG-3 cells at 4h after H(2)O(2) treatment, while there was little to no decrease in SIRT1 protein expression
17586029	The purpose of this study was to determine whether activation of the p53 and retinoblastoma (Rb) pathway by HPV-16 E6 and E7 repression was responsible for apoptosis and senescence of cervical cancer cells and to explore the potential of an antisense RNA (AS) transcript for gene therapy of cervical cancer
17586029	Furthermore, the downregulation of HPV-16 E6 and E7 by 16AS transfection resulted in remarkable increase of both p53 expression and hypophosphorylated p105Rb level in SiHa cells
17573854	This explains the unusual presence of wild type P53, characteristic of this type of solid cancer
17562874	Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS)
17555746	Molecular chaperones regulate p53 and suppress senescence programs
17555746	Recent findings demonstrate that specific depletion of individual chaperones, including various members of the Hsp70 family, small heat shock proteins, or VCP/p97, leads to activation of p53 pathway and subsequently triggers cellular senescence
17555746	Here, we discuss a possibility that in cancer cells high levels of chaperones serve to keep the p53 signaling under control, thus allowing cancer cells to evade the default senescence and form tumors
17538933	Restoration of p53 function: a new therapeutic strategy to induce tumor regression
17538933	Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies
17538933	To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma
17538933	We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions
17538933	The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines
17538933	Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth
17535972	These double-mutant mice survived longer than NHEJ/p53 double-null mice and, remarkably, were completely tumor free
17533371	Amyloid-beta precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress
17533371	The tumor suppressor p53 is a key modulator of the cellular stress response, inducing cell-cycle arrest, apoptosis, senescence and cell differentiation
17533371	To evaluate further the molecular mechanism underlying p53 function, the transcriptional profiles of proliferating and senescent WI-38 cells, both wild-type p53 expressers and counterparts with an inactivated p53, were compared by DNA microarray analysis
17533371	APLP1 was confirmed to be a novel transcriptional target of p53 by in vivo and in vitro characterization of a p53 responsive element found in the first intron of the APLP1 gene locus
17532297	Because hMSCs were induced cellular senescence due to long-term culture, FGF-2 decreased the percentage of senescent cells and suppressed G1 cell growth arrest through the suppression of p21(Cip1), p53, and p16(INK4a) mRNA expression levels
17512465	The induction has been largely attributed to the activation of p53
17500067	Mechanistic studies of MDM2-mediated ubiquitination in p53 regulation
17500067	As a central regulator for cell cycle arrest, apoptosis, and cellular senescence, p53 requires multiple layers of regulatory control to ensure correct temporal and spatial functions
17500067	It is well accepted that Mdm2-mediated ubiquitination plays a crucial role in p53 regulation
17500067	In addition to proteasome-mediated degradation, ubiquitination of p53 by Mdm2 acts a key signal for its nuclear export
17500067	Nuclear export has previously been thought to require the disassociation of the p53 tetramer and exposure of the intrinsic nuclear export signal
17500067	To elucidate the molecular mechanism of degradation-independent repression on p53 by Mdm2, we have developed a two-step approach to purify ubiquitinated forms of p53 induced by Mdm2 from human cells
17500067	Surprisingly, however, we found that ubiquitination has no effect on the tetramerization/oligomerization of p53, arguing against this seemingly well accepted model
17500067	Moreover, nuclear export of p53 alone is not sufficient to completely abolish p53 activity
17500067	Ubiquitination-mediated repression of p53 by Mdm2 acts at least, in part, through inhibiting the sequence-specific DNA binding activity
17500067	Thus, our results have important implications regarding the mechanisms by which Mdm2 acts on p53
17482128	This work shows that telomere-induced senescence is as effective as apoptosis in reducing cancer incidence and is mediated by the tumor suppressor p53
17460194	Knocking down p53 with siRNA does not affect the overexpression of p21WAF-1 after exposure of IMR-90 hTERT fibroblasts to a sublethal concentration of H2O2 leading to premature senescence
17460194	The induction of stress-induced premature senescence (SIPS) was associated with a transient increase in DNA-binding activity of p53 and an increased expression of p21(WAF-1)
17452980	Acetylation is thought to be a key event for p53 activation
17452980	Expression of the N-terminal domain of hAda3 that binds p53 but not p300 blocked p14ARF-induced p53 acetylation and protected MECs from senescence
17452980	Consistent with these findings, the human papillomavirus 16 E6 mutant Y54D, which selectively targets hAda3 but not p53 for degradation and protects MECs from p14ARF-induced senescence, inhibited p53 acetylation
17452980	In H1299 cells, hAda3 overexpression increased p300-mediated p53 acetylation, which conversely decreased following small interfering RNA (siRNA) knockdown of hAda3
17452980	Moreover, depletion of hAda3 by siRNA inhibited endogenous p53 acetylation and accumulation of p21cip1 in response to ectopic p14ARF
17452980	These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence
17447021	The results revealed that, compared with control cells, the WI-38 cells in which p19ARF gene was introduced showed significant up-regulation of p53 and p21 expression level, decrease of cell generation by 10-12 generations, decline of cell growth rate with cell cycle being arrested at G1 phase, increase of positive rate of senescent marker SA-beta-gal staining, and decrease of mitochondrial membrane potential
17433785	Loss of p53 abrogated the short telomere response
17428679	Here, we have used indirect immunofluorescence and confocal microscopy to describe various forms of a novel nuclear PML compartment associated with nucleoli that is found under growth-permitting conditions in human mesenchymal stem cells (hMSC) and skin fibroblasts but not in several immortal cell lines with defects in the p53 and pRb pathways
17409421	Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity
17409421	Thus, we sought to characterize the distinct roles of HDACs in the p53 pathway
17409421	Through the use of stable MCF7 cell lines which inducibly express short hairpin RNA targeting HDAC2, we found that HDAC2 plays important roles in the p53 pathway
17409421	We found that the enhancement was due to increased p53-DNA binding activity but not alterations in p53 stability or posttranslational modification(s)
17409421	Thus, for the first time, our data suggest that HDAC inhibitors function through the p53 pathway, at least in part, by activating p53-DNA binding activity
17396137	We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice
17396137	Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase
17382201	No significant changes in p53 mRNA and protein levels were detected among embryos derived from both oxygen tensions
17382201	Taken together, these results demonstrate that p66shc, but not p53, is significantly more abundant in an embryo population that exhibits higher frequencies of embryo arrest and quantities of intracellular ROS
17351335	Because p53 inactivation may limit the effectiveness of radiation therapy for localized prostate cancer, it is important to understand how this gene regulates clonogenic survival after an exposure to ionizing radiation
17351335	Here, we show that premature cellular senescence is the principal mode of cell death accounting for the radiosensitivity of human prostate cancer cell lines retaining p53 function
17351335	Conversely, inheritance of wild-type p53 by prostate cancer cells lacking a functional allele of this gene (i
17351335	Our data provide evidence that mutations of even one p53 allele may be sufficient to alter their clonogenic fate
17351335	In addition, they support the idea that the p53 pathway can be used as a specific target for enhancing the radiosensitivity of prostate cancer cells
17351335	Activation of p53 by the drug nutlin-3 is shown to be an effective radiosensitizer of prostate cancer cells retaining functional alleles of p53 and this effect was entirely attributable to an increased induction of p53-dependent cellular senescence
17332504	Dynamic regulation of p53 subnuclear localization and senescence by MORC3
17332504	The tumor suppressor p53 is a key transcriptional factor regulating the induction of cellular senescence by oncogenic signals
17332504	The activity of p53 is regulated by recruitment into promyelocytic leukemia (PML)-nuclear bodies (NBs) as well as by stabilization through posttranslational modifications such as phosphorylation and acetylation
17332504	Here we found that MORC3 (microrchidia3)-ATPase activated p53 and induced cellular senescence in normal human and mouse fibroblasts but not p53-/- fibroblasts
17332504	Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-/- fibroblasts
17332504	These results suggest that MORC3 regulates p53 activity and localization into PML-NBs
17332370	Down-regulation of Hsp72 in certain cancer lines triggered cell senescence associated with activation and stabilization of p53 and induction of the cell cycle inhibitor p21
17332370	Effects of Hsp72 depletion on senescence and p53 did not result from a proteotoxic stress, DNA instability, or activation of ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related pathways
17332370	Instead, depletion of Hsp72 reduced stability and activity of the p53 inhibitor Hdm2
17297463	A body of evidence indicates that ARF also possesses growth suppression functions independent of p53, the mechanism of which is not well understood
17297463	Wild-type ARF, but not ARF mutant defective in MDM2 interaction, stabilizes Rb and inhibits colony foci formation independent of p53
17297463	Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development
17291568	Reassessing the role of p53 in cancer and ageing from an evolutionary perspective
17291568	The gene p53 has been fashioned as the guardian of the genome and as prototype of the tumour suppressor gene (TSG) whose function must be inactivated in order for tumours to develop
17291568	The ubiquitous expression of truncated p53 protein isoforms, results in "premature ageing" of laboratory mouse strains engineered for expressing such isoforms
17291568	These facts have been construed in the argument that p53 evolved in order to protect organisms with renewable tissues from developing cancer yet, because p53 is also an inducer of cellular senescence or apoptosis after extensive DNA damage, it becomes a limiting factor for tissue renewal by depleting tissues from stem/precursor cells thus leading to whole-organism ageing
17291568	From that point of view p53 displays antagonist pleiotropy contributing to the establishment of degenerative diseases and ageing
17291568	The evolutionary perspective indicates that p53 evolved so as to play a subtle but very important role during development while its role as a TSG is only important in animals that are protected from most sources of extrinsic mortality, thus suggesting that p53 was primarily selected for its developmental role and not as a TSG
17291568	Therefore no real antagonist pleiotropy can be attached to p53 functions and their relationship with whole-organism ageing might be a laboratory artefact
17276372	BACKGROUND: Various forms of cellular stress can activate the tumour suppressor protein p53, an important regulator of cell cycle arrest, apoptosis, and cellular senescence
17276372	Cells infected by human herpesvirus 6B (HHV-6B) accumulate aberrant amounts of p53
17276372	OBJECTIVES: The aim of this study was to investigate the role of p53 accumulation in the HHV-6B-induced cell cycle arrest
17276372	STUDY DESIGN: The role of p53 was studied using the p53 inhibitor pifithrin-a, and cells genetically deficient in functional p53 by homologous recombination
17276372	RESULTS: In response to HHV-6B infection, epithelial cells were arrested in the G1/S phase of the cell cycle concomitant with an aberrant accumulation of p53
17276372	The presence of pifithrin-a, a p53 inhibitor, did not reverse the HHV-6B-induced cell cycle block
17276372	CONCLUSIONS: HHV-6B infection inhibited host cell proliferation concomitantly with p53 accumulation, but importantly the block in cell cycle occurred by a pathway independent of p53
17266044	The results implicate ZNF217 as an ovarian oncogene, which is detrimental to senescing normal OSE cells but contributes to neoplastic progression in OSE with inactivated p53/RB
17254959	They show that the p38-regulated/activated protein kinase (PRAK) induces senescence downstream of oncogenic Ras by directly phosphorylating and activating the tumor-suppressor protein p53
17251933	Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
17251933	Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies
17251933	To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma
17251933	We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions
17251933	The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines
17251933	Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth
17251932	Restoration of p53 function leads to tumour regression in vivo
17251932	Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance
17251932	Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues
17251932	The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas
17251932	These results support efforts to treat human cancers by way of pharmacological reactivation of p53
17242198	Cellular senescence is an irreversible proliferation arrest triggered by short chromosome telomeres, activated oncogenes, and cell stress and mediated by the pRB and p53 tumor suppressor pathways
17242198	Significantly, translocation of HIRA to PML bodies occurs in the absence of functional pRB and p53 tumor suppressor pathways
17242198	However, our evidence indicates that downstream of HIRA's localization to PML bodies, the HIRA/ASF1a pathway cooperates with pRB and p53 to make SAHF, with the HIRA/ASF1a and pRB pathways acting in parallel
17234816	The results show that, in younger cells, ILK overexpression induces larger cell shapes, lower proliferation capacity, and higher levels of enzymatic beta-galactosidase activity, and increases basal p53 and p21 protein levels, whereas knock-down of ILK prevents phenotypic changes typical of senescence in aging cells
17227869	Cdc42GAP-/- mouse embryonic fibroblasts and/or tissues display reduced population doubling, significantly dampened DNA damage repair activity after DNA-damaging agent treatment, accumulated genomic abnormalities, and induction of p53, p16Ink4a, p21Cip1, and senescence-associated beta-galactosidase expressions
17227869	Furthermore, Cdc42 activation is sufficient to promote a premature cellular senescence phenotype that depends on p53
17210095	AIM: To observe the variation of renal tubular epithelial cells in p53(+/+) and p53(-/-) mice with young or old age at different time after kidney ischemia/reperfusion injury (IRI), and to investigate the contribution of p53 gene in the variation
17210095	METHODS: p53(+/+) and p53(-/-) male mice at age of 2 and 12 months were made ischemic by clamping left renal hila for 45 min
17210095	RESULTS: Renal tubule necrosis was more severely in p53(-/-) mice and aged mice compared to p53(+/+) mice and young mice (P<0
17210095	Apoptotic cells in p53(+/+) mice increased obviously compared to p53(-/-) mice (P<0
17210095	In p53 (-/-) and p53(+/+) aged mice, both kindeys had positive staining for SA-beta-gal activity at 0 d after IRI, but the level of the activity in p53(-/-) mice was much more lower than that in p53(+/+) mice (P<0
17210095	Positive stain of nuclear PCNA in p53(+/+) young mice had no statistical significance compared to p53(+/+) aged mice (P>0
17210095	But in p53(-/-) mice, significant positive staining for PCNA was tested, especially in young mice and in IRI kidneys (P>0
17210095	Correlation analysis between senescent and apoptotic cells in aged mice was made at 1 d after IRI, then striking negative correlation was found between both of them in p53(+/+) mice (r=-0
17172853	Recently, we described that the p53 target gene plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of replicative senescence
17172853	Both uPA and PAI-1 are expressed in senescent cells and their relative abundance controls proliferation downstream of p53
17172844	Posttranslational modification such as phosphorylation of p53 plays important roles in activating p53 responses to various cellular and genotoxic stresses
17172844	Cell line studies have shown that phosphorylation of Ser46 is correlated with the activation of p53 apoptotic activity
17172844	To address the physiological roles of Ser46 phosphorylation, we employed homologous recombination and LoxP/Cre-mediated deletion to introduce Ser46 to Ala missense mutation into the human p53 knock-in (HUPKI) allele in mice (p53hki(S46A))
17172844	Consistent with this finding, transcription of p53 target apoptotic genes is preferentially affected by S46A mutation after DNA damage
17166668	Jekyll and Hyde, the p53 protein, pleiotropics antagonisms and the thrifty aged hypothesis of senescence
17166668	One of the proposed examples is p53, a gene that plays a pivotal role in the cell stress response
17166668	In this issue the p53 candidature to be an antagonistic pleiotropic gene is revisited
17158953	The expression of N-terminally enhanced green fluorescent protein (EGFP)-tagged histone H1 induces premature senescence phenotypes, including increased levels of phosphorylated p53, p21, and hypophosphorylated Rb, and a decrease in the chromatin-bound endogenous histone H1 level but not in p16 level accumulation or SAHF formation
17126333	Activation of p53 by oxidative stress is unaffected despite a marked decrease in expression of platelet-derived growth factor alpha-receptor
17092342	Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence
17084559	The discrepancy might have resulted from the p53 status
17084559	We demonstrated the potential contribution of p53-dependent mechanisms to inhibit lung tumor growth and increase radiosensitization using H1299 transfected with p53 in vitro and in vivo
17084559	An increased p53 level attenuated the capacity of the cells for metastasis by decreasing vascular endothelial growth factor and induced radiosensitization by increased apoptosis and cell senescence and by regulating intracellular reactive oxygen species
17077613	The importance of p53 and p21 activation/induction i now well accepted in the signal transduction process from telomere shortening to growth arrest, but the precise mechanism is largely unknown as yet
17034355	The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53
17032649	Finally, phospho-Ser(15) p53 was significantly increased in L61Rac1 and Rac1(-/-) cells, and genetic deletion of p53 from these cells readily reversed the senescence phenotype, indicating that Rac1 is functionally dependent on p53 in regulating cell senescence
17032649	Taken together, our results show that Rac1 activity serves as a regulator of cell senescence through modulation of cellular ROS, genomic stability, and p53 activity
17016587	The characteristics of proliferation and metastasis were shown by PCNA (proliferating cell nuclear antigen), and nm23 and cell cycle-related genes, such as p16, p21, p53 and pRb, were analyzed by RT-PCR and immunohistochemistry
17016587	The cell cycle-related genes, such as p16, p21, p53 and pRb, were not detected in F6 cells, while the expression of hTRAP and BMI-1 was significantly higher
17015432	CPEB cannot stimulate senescence in MEFs lacking the tumor suppressors p53, p19ARF, or p16(INK4A); however, the mRNAs encoding these proteins are unlikely targets of CPEB since their expression is the same in wild-type and KO MEFs
17014852	Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway
17014852	Knockdown of p53 in the Klotho attenuated MRC-5 cells restores normal growth and replicative potential
17014852	These results demonstrate that Klotho normally regulates cellular senescence by repressing the p53/p21 pathway
16951143	Replicative life span in normal human cells can be extended by inactivation of the tumor suppressor gene p53 or its direct target, the cyclin-dependent kinase inhibitor p21, suggesting a direct role for this pathway in senescence
16951143	However, p53 recruitment to promoters of target genes during replicative senescence has not been shown in live cells
16951143	In this study, we used chromatin immunoprecipitation to determine that p53 preferentially occupied the promoters of growth arrest genes p21 and GADD45 in senescent normal human diploid fibroblasts but not the promoters of other target genes that recruited p53 following doxorubicin-induced DNA damage, such as apoptosis regulators TNFRSF10b, TNFRSF6, and PUMA
16951143	This differential recruitment of p53 in senescent versus doxorubicin-treated fibroblasts was accompanied by differences in post-translational modification of p53
16951143	These data provide mechanisms for both the growth arrest mediated by p53 and the resistant nature of senescent cells to apoptosis despite p53 activity
16939485	Furthermore, in the treated cells growing beyond the original Hayflick limit, the levels of p53, p21WAF1, and phospho-Rb proteins were similar to those in actively proliferating cells
16936745	In this respect, Rb2/p130 functions are connected to signaling pathways induced by p53, which is a master regulator in cellular senescence
16929177	The role of p53 in atherosclerosis
16929177	Although the role of the tumor suppressor gene p53 is well known in cancer, recent studies have highlighted a fundamental role for p53 in regulating cells in the advanced atherosclerotic plaque, the major cause of heart attacks and stroke
16929177	In particular, p53 is activated in the complex environment of the plaque, in part by DNA damage within the lesion, and regulates growth arrest, cell senescence and apoptosis of vascular smooth muscle cells (VSMCs)
16929177	The role of endogenous p53 has been determined using p53 knockout in mice developing advanced atherosclerosis, using bone marrow transplant to separate effects on blood cells from vessel wall cells
16929177	In particular, recent studies have identified a role for endogenous p53 in protection of VSMCs from apoptosis, trans-differentiation of bone marrow stromal cells into VSMCs in atherosclerosis, and altering the mode of cell death in the plaque
16920112	Phosphatidylcholine-specific phospholipase C, p53 and ROS in the association of apoptosis and senescence in vascular endothelial cells
16920112	Here, to explore whether PC-PLC is involved in the association of apoptosis and senescence in VECs, we analyzed p53 expression and intracellular reactive oxygen species (ROS) levels in young and senescent VECs before and after inhibiting PC-PLC activity
16920112	The results showed that suppressing PC-PLC inhibited apoptosis and the elevation of p53 expression induced by apoptosis in young cells, but not in senescent cells, and that inhibiting PC-PLC depressed intracellular ROS levels both in young and senescent cells
16920112	Its function might be closely related to the level of p53 in VECs
16894028	Apoptosis inhibition by the human DEK oncoprotein involves interference with p53 functions
16894028	Cell death in response to DEK depletion was accompanied by increased protein stability and transcriptional activity of the p53 tumor suppressor and consequent upregulation of known p53 target genes such as p21CIP and Bax
16894028	Finally, expression of a dominant negative p53 miniprotein inhibited DEK RNA interference-induced p53 transcriptional induction, as well as cell death, thus directly implicating p53 activation in the observed apoptotic phenotype
16894028	These findings suggest a novel role for DEK in cellular survival, involving the destabilization of p53 in a manner which is likely to contribute to human carcinogenesis
16882877	The induction of WI38 cell senescence by Etop was associated with p53 activation and could be attenuated by down-regulation of p53 using alpha-pifithrin (alpha-PFT) or p53 small interference RNA (siRNA)
16882877	However, inhibition of p53 with alpha-PFT or p53 siRNA or JNK with SP600125 (1,9-pyrazoloanthrone) failed to protect WI38 cells from BU-induced senescence
16880792	The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21
16880792	Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed
16880792	In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining
16862142	Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence
16862142	However, little is known about the downstream target genes of p53 in this growth-limiting response
16862142	Here, we report that suppression of the p53 target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference (RNAi) leads to escape from replicative senescence both in primary mouse embryo fibroblasts and primary human BJ fibroblasts
16862142	Our data indicate that PAI-1 is not merely a marker of senescence, but is both necessary and sufficient for the induction of replicative senescence downstream of p53
16840774	We found that cigarette smoke stopped proliferation of lung fibroblasts and upregulated two pathways linked to cell senescence (a biological process associated with cell longevity and an inability to replicate), p53 and p16-retinoblastoma protein pathways
16840774	The decrease in proliferation was accompanied by increased ATM, p53, and p21 activity
16821141	In addition, the upregulation of WAF1 and p53 related to biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damage such as oxidative stress
16793547	Here we show that overexpression of the E3 SUMO ligase PIASy in normal human fibroblasts recruits the p53 and Rb tumor suppressor pathways to provoke a senescence arrest
16793547	PIASy stimulates sumoylation and transcriptional activity of p53 and increases Rb-dependent corepression through recruitment to E2F-responsive promoters
16778193	Promyelocytic leukemia (PML) has been implicated in a variety of functions, including control of TP53 function and modulation of cellular senescence
16763167	We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart
16757976	Mouse p53 is phosphorylated at Ser18 and Ser23 after DNA damage
16757976	To determine whether these two phosphorylation events have synergistic functions in activating p53 responses, we simultaneously introduced Ser18/23 to Ala mutations into the endogenous p53 locus in mice
16757976	While p53(S18A) mice are not cancer prone, p53S18/23A mice developed a spectrum of malignancies distinct from p53S23A and p53(-/-) mice
16757976	Interestingly, Xrcc4(-/-)p53S18/23A mice fail to develop tumors like the pro-B cell lymphomas uniformly developed in Xrcc4(-/-) p53(-/-) animals, but exhibit developmental defects typical of accelerated ageing
16708569	In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions
16652144	Moreover, p53 activation itself contributes to ROS accumulation
16652144	Inhibition of Chk1 by an RNAi approach resulted in an increase in cell death in p53-null cells, showing that the Chk1-dependent G(2) checkpoint protected cells that lacked a functional p53 pathway from oxidative stress
16641528	The alteration of the TP53 gene or posttranslational modification in the p53 protein can alter its response to cellular stress
16641528	The molecular archaeology of the TP53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of human cancer
16641528	The spectrum of somatic mutations in the TP53 gene implicates environmental carcinogens, and both endogenous agents and processes in the etiology of human cancer
16626549	OBJECTIVE: To investigate whether p53 pathway participates in the effect of emodin on vascular smooth muscle cell proliferation
16626549	DNA synthesis was determined by (3)H-thymidine corporation, cell cycle was analyzed by FACS, the p53 protein level was measured by Western blot and cDNA expression array technology was used to demonstrate the effect of emodin on the simultaneous expression of a large number of genes in cultured vascular smooth muscle cells
16626549	The mRNA and protein levels of p53 were up-regulated in a concentration-dependent manner
16626549	CONCLUSIONS: The p53 pathway in VSMC was activated post emodin exposure in a concentration-dependent manner and which might be responsible for the observed antiproliferative effects of emodin in vascular smooth muscle cells
16608399	Several genes in the p53, Rb, and ING (inhibitor of growth) pathways affect cell senescence and are capable of regulating gene expression through chromatin remodeling
16603702	Studies support a central role for Rb protein in controlling this process after it receives senescent signals from the p53 and p16 pathways
16596252	Importantly, it appears that E2F1 depletion-induced cancer cell senescence is not reliant on the integrity of either Rb or p53
16569765	While ATL patients carrying a wild-type p53 enter remission following treatment with AZT, those with a mutated p53 did not respond, and patients' disease relapse was associated with the selection of a tumor clone carrying mutated inactive p53
16567311	This observation provides a mechanistic explanation for the rarity of p53 mutations in neuroblastomas
16557269	The P53 pathway: what questions remain to be explored
16557269	The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals
16557269	In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways
16520380	Unlike its homologues ING1b and ING2, ING3-increased apoptosis was independent of functional p53
16516887	Relocalization occurs concomitantly with interaction with a subset of nuclear proteins, including PCNA, p53 and several regulators of acetylation such as the p300/CBP and PCAF histone acetyltransferases (HATs), as well as the histone deacetylases HDAC1 and hSir2
16513254	Similar to overexpression of oncogenic H-ras in the normal human fibroblast, overexpression of IRF3 in human fibroblast BJ cells was shown to decrease cell growth and increase senescence-associated beta-galactosidase activity by activating a p53 tumor suppressor
16513254	BCNU, a DNA damage agent, further accelerated p53 function and cell death in the IRF3-overexpressed BJ cells compared to control BJ cells, without increased expression of IRF3 target genes
16513254	IRF3 failed to activate p53 function and cell growth inhibition in BJ cells downregulating p53 by RNAi-mediated p53 knockdown
16513254	Furthermore, enforced expression of IRF3 did not show any effect of cell growth inhibition in astrocytes or embryonic fibroblasts derived from the p53(-/-) mouse
16513254	Taken together, the present study indicates that IRF3 should be a novel inducer of cell growth inhibition and cellular senescence through activation of p53 tumor suppressor
16476774	Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy
16457693	The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action
16456675	In addition, as pan-cell cycle regulator TIS21 induces G1/S arrest by pRB dependently and pRB independently and G2/M arrest and cell death in the p53 null tumor cells, and regulates the development of vertebrate patterning in mouse, paraxial mesoderm development in zebrafish, and notochord development in Xenopus
16456675	It has been known that the expression of TIS21 depends on the induction of wt p53 when cells are damaged, however, it can also be upregulated p53 independently by the activation of PKC-delta pathway in tumor cells
16456675	The latter has already been well elucidated; TIS21 inhibits the expression of cyclin D1, thus resulting in the arrest of cells at G1/S phase by pRB and p53 dependent manner
16442104	Treatment of IMR-90 cells with CKII inhibitors 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole and apigenin led cells to acquire a senescent phenotype as judged by the senescence-associated beta-galactosidase marker and overexpression of p53 and p21(Waf-1)
16426144	Previously, we studied the genes dysregulated during immortalization using spontaneously immortalized fibroblasts from patients with Li-Fraumeni syndrome (LFS), who carry a germline mutation in the tumor suppressor gene p53
16325773	The expression of p53 and p21 was lower in Klotho-treated cells
16317088	Some of these functions are at least partially exerted through activation of the p53 transcription factor
16308915	The current studies were designed to characterize the accelerated senescence response to radiation in the breast tumour cell in terms of its dependence on functional p53 and its relationship to telomerase activity, telomere lengths, expression of human telomerase reverse transcriptase (hTERT, the catalytic subunit of telomerase) and human telomerase RNA (hTR, the RNA subunit of telomerase), as well as the induction of cytogenetic aberrations
16308915	Studies were performed in p53 wild-type MCF-7 cells, MCF-7/E6 cells with attenuated p53 function, MDA-MB231 cells with mutant p53 and MCF-7/hTERT cells with constitutive expression of hTERT
16308915	Accelerated senescence in response to ionizing radiation is p53 dependent and associated with telomer dysfunction but is unrelated to changes in telomerase activity or telomere lengths, expression of hTERT and hTR
16308915	In the absence of functional p53, cells are unable to arrest for an extended period, resulting in apoptotic cell death while accelerated senescence in cells expressing p53 is succeeded by proliferative recovery
16258284	The p53 tumor suppressor functions as a sequence-specific DNA-binding transcription factor that promotes antiproliferative responses, including cell cycle checkpoints, cellular senescence and apoptosis
16258284	The precise nature of the p53 transcriptional programs and the complex mechanisms that govern whether or not a cell dies in response to p53 activation remain elusive
16258284	We have recently reported the identification of a new direct p53 target, Ptprv, encoding a transmembrane tyrosine phosphatase
16243918	Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53
16243918	When compared with native collagen, early passage HUVECs showed increased p53, p21(CIP1) (p21), and p16(INK4a) (p16) mRNA expression after exposure to GC
16243918	Transfection of p21 or p53 induced apoptosis in HUVECs
16243918	Next, we suppressed endogenous p53, p21, p16, or retinoblastoma (Rb) gene expression through small interference RNA strategy and investigated their influence in p16- and p21-initiated endothelial cell senescence
16243918	Analysis indicated that suppression of p53 expression can abolish senescence induced by p16 overexpression
16243918	In summary, the p53/p21 pathway is mainly responsible for GC-induced apoptosis, but the coordinated activation of the p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence through a Rb-dependent mechanism
16217555	The subcellular distribution of the p53 tumour suppressor, and organismal ageing
16217555	The p53 protein, the product of a tumour suppressor gene, is a key regulator of cell growth, differentiation and apoptosis
16217555	The activation of p53 is primarily mediated by post-translational modifications that affect its conformation and capacity to bind to several proteins, resulting in its stabilization and enhanced DNA-binding potential
16217555	Another way to regulate the biological function of p53 involves changes in its intracellular distribution
16217555	This paper presents an overview of the role of p53 in cellular senescence and the regulation of p53 activity by its intracellular distribution
16189290	Lower antioxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria, and longevity
16167330	The mammalian ING proteins are candidate tumor suppressor proteins and accordingly can cooperate with p53 to arrest proliferation and induce apoptosis
16123778	Cooperation between p53 and p130(Rb2) in induction of cellular senescence
16123778	To determine pathways cooperating with p53 in cellular senescence when the retinoblastoma protein (pRb)/p16INK4a pathway is defunct, we stably transfected the p16INK4a-negative C6 rat glioma cell line with a temperature-sensitive mutant p53
16123778	Inactivation of p53 in senescent cultures restores the pocket proteins to initial levels and initiates progression into S-phase, but the cells fail to resume proliferation, likely due to DNA damage becoming apparent in the arrest and activating apoptosis subsequent to the release from p53-dependent growth suppression
16123778	The data indicate that p53 can cooperate selectively with p130(Rb2) to induce cellular senescence, a pathway that may be relevant when the pRb/p16INK4a pathway is defunct
16120770	We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway
16120770	We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone
16120770	Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels
16109412	A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells
16107878	Senescence is an irreversible form of G1 arrest that requires the p19ARF/p53 and p16INK4a/pRB pathways and may suppress tumorigenesis in vivo
16107878	C/EBPbeta-/- mouse embryo fibroblasts (MEFs) expressing Ras(V12) continued to proliferate despite unimpaired induction of p19ARF and p53, and lacked morphological features of senescent fibroblasts
16107878	Enforced C/EBPbeta expression inhibited proliferation of wild-type MEFs and also slowed proliferation of p19Arf-/- and p53-/- cells, indicating that C/EBPbeta acts downstream or independently of p19ARF/p53 to suppress growth
16107721	MnSOD overexpression causes up-regulation of p53 and its transcriptional target, the cyclin-dependent kinase inhibitor p21
16107721	Adenovirus-mediated knockdown of p53 by RNA interference rescues MnSOD-overexpressing clones from growth retardation
16107721	These results indicate a pivotal role of p53, but not p21, in the observed effects
16107721	Our data indicate that uncoupling of the electrochemical gradient by increased MnSOD activity gives rise to p53 up-regulation and induction of senescence
16107615	The p53 tumor suppressor plays a key role in organismal aging
16107615	A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53
16093429	Transient transfection of H460 lung cancer cells and human umbilical vascular endothelial cells (HUVEC) with antisense oligonucleotides (ASODN) against MDM2 resulted in a reduced level of MDM2 and increased levels of p21 and p53
16082224	A common polymorphism at codon 72 in p53 gene leads to an arginine to proline aminoacidic substitution which affects in an age-dependent manner the susceptibility of cells to undergo apoptosis after oxidative stress
16082224	We conclude that the functional difference between the two p53 codon 72 alleles exerts a broad impact on the capability of cell from aged people to respond to stressors such as cytotoxic drugs
16079851	The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer
16079851	Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription
16079851	Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency
16079851	Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age
16079851	Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53
16079851	Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours
16079837	Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively
16077192	Moreover, the interaction and cross-talk between p53 and PARP1-1 was discussed
16024017	Their expression levels of p53 and cyclin-dependent kinase inhibitors (CDKI) were about 2-3-fold higher than the control
15916863	Here we show that the highly invasive, tumorigenic human non-small-cell-lung cancer (NSCLC) cells carrying mutated p53 alleles were transfected with herpes simplex virus-thymidine kinase (HSV-tk) cDNA and the selected clone was susceptible to exogenous ganciclovir (GCV)
15916863	These data showed that the GCV-suppressed tumor cell proliferation can be coordinated by cell cycle arrest and cellular senescence in HSV-tk transfectant lacking wild-type p53
15885198	Telomere-initiated senescence or loss of telomere function trigger focal recruitement of protein sensors of the DNA double-strand breaks leading to the activation of the DNA damage checkpoint responses and the tumour suppressor gene product, p53, which in turn induces the cell-cycle inhibitor, p21(WAF1)
15885198	Loss of p53 and pRb function allows continued cell division despite increasing telomere dysfunction and eventually entry into telomere crisis
15885198	These barriers are regulated by telomere shortening and by the p16(INK4a)/Rb and p53 tumour suppressor pathways
15866171	AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration
15865934	Death squads enlisted by the tumour suppressor p53
15865934	In this review we summarise current knowledge of p53 target genes implicated in apoptosis signalling
15838523	The p53 pathway: positive and negative feedback loops
15838523	The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division
15838523	A stress signal is transmitted to the p53 protein by post-translational modifications
15838523	This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis
15838523	The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response
15838523	There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity
15833273	The appearance of these cellular senescence markers was accompanied by significant increases of p21, gadd45 expression and p53 binding activity, as well as a significant decline in DNA repair capability and accelerated telomere shortening
15811427	In addition, cells in these two states exhibited quite distinct time course profiles of the proteins, p53, p21WAF1, and E2F1
15811424	In this study, altered hMSCs were verified to be senescent by their senescence-associated beta-galactosidase (SA-beta-gal) activity and the increased expression of cell cycle regulating proteins (p16(INK4a), p21(Waf1) and p53)
15795472	Role of p53 tumor suppressor in ageing: regulation of transient cell cycle arrest and terminal senescence
15795472	In this study we investigated the function of p53 as a regulator of cell cycle progression in cycling and senescent cells
15795472	Using the conditional temperature-sensitive (ts) mutant we could prevent the detrimental effect of constitutive expression of high levels of wt p53 protein
15795472	Flow cytometric analysis revelaed a maintenance of G1 cell population for a longer time depending on the prolonged expression of wt p53 protein
15795472	However, a spontaneous increase of wt p53 occurring in ageing normal human MRC-5 fibroblasts was associated with irreversible reduction of proliferative potential
15769896	Taken together, these results suggest that reoxygenation induces premature senescence in Fancc-/- BM hematopoietic cells by signaling through p53, up-regulating p21, and causing senescent cell-cycle arrest
15769667	Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis
15743814	Furthermore, cells do not lose their overhangs when they bypass senescence after the inactivation of p53 and Rb
15743671	The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence
15742196	Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts
15742196	Noticeably, senescent fibroblasts markedly produced p53 molecules and anchored them to vimentin-cytoskeleton in the cytoplasm
15742196	The vimentin-anchored p53 was detected with antibody PAb240 that specifically recognizes a conformation variant of p53
15742196	A GFP-tagged wild type p53 cDNA was expressed by transfection and shown also to be retained in the cytoplasm in senescent cells, suggesting that p53 is structurally modified to be recognized by PAb240 and anchored to vimentin filaments
15742196	We discuss the correlation of the marked alteration of cytoskeleton and senescent cells' diminished proliferation and migration, as well as the significance of cytoskeletal anchorage of tumor suppressor p53
15741276	We found that the down-regulation of FOXO3a RNA and protein in HDFs induced many senescent phenotypes, including changes in cell morphology, increases in population doubling times, senescence-associated beta-galactosidase staining and the cellular reactive oxygen species, and up-regulation of p53/p21 protein expression
15734683	This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism
15723042	Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function
15716376	Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53
15716376	Importantly, similar results were observed in human cancer cells lacking functional p53 and pRB family proteins
15711569	We have recently reported that the transcriptional activator p53 can trigger ICAM-1 expression in an nuclear factor-kappa B (NF-kappaB)-independent manner (Gorgoulis et al, EMBO J
15711569	As p53 exhibits an increased transcriptional activity in senescent cells, we investigated whether p53 activation is responsible for the senescence-associated ICAM-1 overexpression
15711569	We also demonstrate in atherosclerotic lesions the presence of cells coexpressing activated p53, ICAM-1, and stained with the senescence-associated beta-galactosidase, a biomarker of replicative senescence
15685514	Characteristics of senescent mononuclear cells include telomere length shortening, increased p53 expression, CD14dim/CD16bright expression, and interleukin overproduction
15685514	Expression of p53, CD14/CD16, and intracellular cytokine production (interleukin-1beta [IL-1beta], IL-6, and IL-4) was evaluated by means of flow cytometry using specific antibodies
15685514	RESULTS: Features of senescence were found in a subpopulation of mononuclear cells: (1) accelerated telomere shortening, (2) increased p53 expression, (3) CD14dim/CD16bright expression, and (4) cytokine overproduction (IL-1beta, IL-6, and IL-4)
15665293	Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis
15664728	Replicative senescence in sheep fibroblasts is a p53 dependent process
15664728	Senescent skin fibroblasts had increased levels of p53 and p21WAF1 compared to young cells
15664728	Incubation of senescent cells with siRNA duplexes specific for p53 suppressed p53 expression and allowed the cells to re-enter the cell cycle
15657429	Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways
15657429	The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally
15657429	To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb
15610769	X facilitates the formation of DNA damage foci around uncapped telomeres, and this in turn activates downstream kinases Chk1 and Chk2 and, eventually, p53
15601862	However, the silencing function is independent of the presence of p53
15574883	In addition to DUSP1 and known p53 and E2F targets, a number of genes such as PHLDA1, NR4A3, and a novel splice variant of STAC were implicated in senescence
15557822	But, the expression of p21(Waf1) was increased, while p27(Kip1) and p53 were not detected in hydroxyurea treated rat hepatoma cells
15532096	It is known to bind to and inactivate wild-type tumour suppressor protein p53 and influences the Ras-Raf-MAPK pathway
15530855	In human fibroblasts, suppressing both the p53 and pRb pathways is necessary to bypass replicative senescence as well as senescence induced by ectopic expression of a dominant negative form of the telomere repeat binding factor 2, TRF2(DN)
15530855	We recently reported that exposure to oligonucleotides homologous to the telomere 3' overhang (T-oligos) activates both the p53 and pRb pathways and leads to senescence in primary human fibroblasts
15530855	To further characterize T-oligo-induced senescence, we compared established isogenic fibroblast cell lines lacking functional p53 and/or pRb pathways to the normal parental line
15530855	Here, we report that, as in physiologic senescence, inactivation of both the p53 and pRb pathways is necessary to suppress T-oligo-induced senescence
15467458	On the other hand, in a tumor cell in which neither the p53 nor pRb pathway is intact, shortened telomeres could initiate chromosome instability and promote tumorigenesis A major issue in telomere research is to understand how shortened dysfunctional telomeres can regulate the onset of cellular senescence
15381105	Cells from old donors also demonstrated features characteristic of cellular senescence associated with phosphorylation of p38MAPK but only a modest increase in p53
15379854	Activation of the tumor suppressor protein p53 contributes to cellular senescence
15379854	As glycogen synthase kinase-3 (GSK3) was recently found to interact with p53 and contribute to the actions of p53, this study examined whether GSK3 accumulated in the nucleus and associated with p53 in senescent cells
15379854	Co-immunoprecipitation experiments demonstrated that GSK3beta and p53 formed a complex in the nucleus
15379854	Lithium treatment reduced the senescence-associated accumulation of p53 and caused cells to enter a reversible quiescent state
15379854	These results indicate that a portion of the p53 that is activated in senescent cells is modulated by its association with GSK3beta in the nucleus, an association that is known to facilitate the actions of p53 and that may contribute to senescence
15377661	This was followed by sequential induction of p53, p21, and p16
15377661	Increase in hypophosphorylated Rb and induction of p53 and p21 by a single stress treatment was transient, whereas sustained induction or dephosphorylation were achieved by a second stress
15302571	Expression profiles of p53 and p66shc during oxidative stress-induced senescence in fetal bovine fibroblasts
15302571	Both the tumor suppressor protein p53 and the stress-response protein p66(shc) are suggested to regulate the molecular events associated with senescence
15302571	This study was undertaken to investigate the effect of different oxygen tensions and oxidative stress on cell longevity and to establish the role of p53 and p66(shc) in cells undergoing senescence
15302571	Taken together, our results show an effect of oxidative stress on the replicative life span of fetal bovine fibroblasts as well as an involvement of p53, serine 20-p53 phosphorylation and p66(shc) in senescence
15247038	Senescent cells are characterized by the activation of the tumor suppressor protein p53 and consequently their inability to proliferate
15247038	Although the role of the nuclear factor-kappa B (NF-kappa B) signaling cascade is crucial in ICAM-1 activation, we have shown that p53 directly activates the expression of ICAM-1 in an NF-kappa B-independent manner
15247009	Insights into aging obtained from p53 mutant mouse models
15247009	One such longevity assurance gene is the tumor suppressor p53, a transcription factor that is mutated or dysregulated in most human cancers
15247009	Early studies have linked p53 to the induction of cellular senescence, whereas recent reports implicate it as a potential regulator of organismal aging
15247009	We have shown by gene inactivation studies that loss of p53 function enhances tumor susceptibility and reduces longevity in the mouse
15247009	A recent serendipitously generated p53 mutant allele resulted in a hypermorphic version of p53 that displays increased cancer resistance, yet also mediates decreased longevity
15247009	Molecular studies of the p53 mutant allele product indicate that it induces an increase in p53 activity in both in vitro and in vivo contexts
15247009	Our model is that enhanced growth inhibitory activity of p53 produces an earlier loss of the ability of stem cells to produce adequate numbers of progenitor and mature differentiated cells in each organ
15247009	Currently, we are performing stem cell functional assays from p53 mutant and wild-type mice to test this model
15247009	One challenge for the future will be to find ways to manipulate p53 function to provide increased cancer resistance, yet still enhance overall organismal longevity
15242773	The induction of HDF senescence was associated with an activation of p53, increased expression of p21Cip1/WAF1, and hypophosphorylation of retinoblastoma protein (Rb), while no changes in the expression of p16Ink4a, p27Kip1, and p14Arf were observed
15208672	Activated p53 suppresses the histone methyltransferase EZH2 gene
15208672	This process is regulated at critical steps by the tumor suppressor p53
15208672	Activated p53 suppressed EZH2 gene expression through repression of the EZH2 gene promoter
15208672	This activity of p53 requires intact p53 transactivation and DNA binding domains
15208672	Furthermore, the repression of EZH2 promoter by p53 is dependent on p53 transcriptional target p21(Waf1) inactivating RB/E2F pathways
15208672	Activated p53 suppresses EZH2 expression, suggesting a further role for p53 in epigenetic regulation and in the maintenance of genetic stability
15208672	Suppression of EZH2 expression in tumors by p53 may lead to novel approaches to control cancer progression
15195682	Metabolic gene polymorphisms and p53 mutations in healthy centenarians and younger controls
15195682	To obtain insights into the genetic mechanisms of ageing, we studied the frequency of the simultaneous presence of polymorphisms in phase I and phase II genes and of several p53 germline mutations in a group of 66 nonagenarians and centenarians in good health, selected from a larger sample of a multicentre Italian study in Northern Italy, and in a sample of 150 young healthy volunteers of the same ethnic group
15195682	We found a statistically significant difference in the frequency of 1the GSTT1 deletion and the p53 genotypes: the absence of any p53 polymorphisms and of GSTT1 deletion, and the simultaneous presence of the three p53 polymorphisms and of GSTT1 deletion, were much more frequent in young subjects than in centenarians (41
15195682	One hypothesis to explain this difference is that subjects with both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens and may have reduced DNA repair ability, and thus are more at risk for cancer
15195682	Another possible explanation is that both metabolic genes and p53 act on pathways related to cell ageing and death, and therefore certain composite genetic patterns could represent a generic mechanism of protection against ageing, not just against the development of chronic diseases
15171255	Dynamics of the p53 acetylation pathway
15171255	The p53 tumour suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress
15171255	However, p53 is a short-lived protein and its activity is maintained at low levels in normal cells
15171255	Interestingly, two additional regulators have also been identified in the p53 acetylation pathway
15171255	PID/MTA2 is a p53-interacting protein that induces p53 deacetylation by recruiting the HDAC1 complex
15171255	Subsequent work has also identified Sir2alpha, a NAD-dependent histone deacetylase that can attenuate p53 transcriptional activity through deacetylation
15171255	The prominence of deacetylase activity on p53 certainly raises the defining question of its physiological purpose
15171255	It is likely that deacetylation proxides a quick acting mechanism to stop p53 function once transcriptional activation of target genes is no longer needed
15171255	Furthermore, we also try to define the functional consequence of p53 acetylation at the molecular level
15171255	Finally, we propose a model regarding the differential roles of HDAC1 and Sir2alpha in the regulation of p53 function
15156563	Oncogenic activation in primary murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the p53 tumor suppressor pathway
15156563	Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence
15156563	In contrast, coexpression of oncogenic ras with p53 produced an irreversible cell cycle arrest that displayed features of cellular senescence
15156563	Introduction of a conditional murine p53 allele (p53val135) into double p53/p21-null mouse embryonic fibroblasts showed that p21waf1 was not required for this effect, since p53-/-;p21-/- double-null cells undergo terminal growth arrest with features of senescence following coexpression of oncogenic Ras and p53
15156563	Our results indicate that oncogenic activation of the Ras pathway in murine fibroblasts converts p53 into a senescence inducer through a p21waf1-independent mechanism
15149599	Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)
15149599	Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest
15147944	A high percentage of replicative senescent cells were positive for senescence-associated beta-galactosidase activity, and displayed elevated levels of p21 and p53 proteins
15147944	In vivo experiments disclosed that CTGF, pSmad, and p53 were constitutively expressed at basal levels in up to 18-month-old rat liver, and expression was significantly up-regulated in 24-month-old rat tissue
15138376	In this Review article, we categorize cellular senescence into two types, which for simplicity we term intrinsic or extrinsic senescence, focus on the differences between human and mouse cells, and discuss the roles of the p53 and pRb tumor suppressor pathways in cellular senescence
15130753	Replicative senescent cells showed a decreased ability to induce cell proliferation, probably due to the increased expression of the p53 protein and the decreased expression of the PCNA protein, and also showed increased expression of MMP-1, and decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and procollagen
15119525	We further show that animal interventions appearing to alter senescence, p53 mutation and melatonin dosing, support the prediction that increasing senescence rate reduces cancer while reducing lifespan, and vice versa
15116721	Since its discovery 25 years ago, the p53 protein has emerged as a key tumor suppressor protein at the crossroads of cellular stress response pathways
15116721	Through these pathways, which can lead to cell-cycle arrest, DNA repair, cellular senescence, differentiation and apoptosis, p53 facilitates the repair and survival of damaged cells or eliminates severely damaged cells from the replicative pool to protect the organism
15116721	Because of these dynamic and multiple functions of p53, which are largely lost following mutations in the gene encoding p53, this molecule continues to be studied intensively in biomedical research, including the fields of toxicology and pharmacology
15116721	In this article, we briefly review the first 25 years of research on p53
15111320	To clarify roles during squamous differentiation (SqD) of endometrial carcinoma (Em Ca) cells, we investigated expression of beta-catenin, as well as cyclin D1, p53, p21WAF1, and PML (promyelocytic leukemia) in 80 cases of Em Ca with SqD areas, in comparison with cell proliferation determined with reference to Ki-67 antigen positivity
15111320	In clinical cases, nuclear beta-catenin accumulation was more frequent in SqD areas, being positively linked with expression of cyclin D1, p53, and p21WAF1, and inversely with Ki-67 and PML immunoreactivity
15111320	Significant correlations of nuclear beta-catenin, cyclin D1, p53, and p21WAF1 were noted between SqD and the surrounding carcinoma lesions
15111320	The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant beta-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML, and activation of beta-catenin-TCF4-mediated transcription determined with TOP/FOP constructs
15040891	The premature senescence changes included high frequency of apoptosis, elevation of p53 expression, loss of membranous gap junctions and reduction of dye-transfer capacity
15013668	Furthermore, we found that while the pro-apoptotic p53 increased, the anti-apoptotic Bcl-2 declined
15004530	Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction
14999681	Here we report the immortalization of primary hepatocytes isolated from p19(ARF) null mice using the rationale that loss of p19(ARF) lowers growth-suppressive functions of p53 and bypasses cellular senescence without losing genetic stability
14980702	Simultaneous induction of p16(INK4a) and p53 was detected in G6PD-deficient but not in normal fibroblasts during H(2)O(2)-induced senescence
14743960	Epidermal growth factor suppresses interferon-induced accumulation of p53 and p21 by using protein kinase C
14743960	The tumor suppressor protein p53 is the most frequently mutated gene in human cancers
14743960	Since its discovery, p53 has evolved from a potential oncogene to the principal tumor suppressor in humans
14743960	Now, p53 is positioned at the vertex of cellular signals warning of threats of genomic damage and oxidative stress
14743960	Under these conditions p53 is phosphorylated by multiple kinases and these phosphorylations not only increase its half-life but also increase its localization in the nucleus
14743960	Pretreatment of ME180S cells with epidermal growth factor (EGF) inhibits IFN-dependent induction of p53 and p21 by protein kinase C dependent pathways
14728717	The G2/M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G0/G1 phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells
14728717	We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon
14728717	The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since p53 mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG
14726476	Gene products implicated in growth arrest and senescence, such as p27Kip1, p53, p16INK4a, and p19ARF, were detected in myocytes of young WT mice, and their expression increased with age
14719074	The p53 protein is a transcription factor with multiple biological activities, including cell cycle arrest and/or apoptosis upon DNA damage, hypoxia and oncogene activation; this requires transactivation or repression of specific target genes by wild-type p53
14719074	To better understand if a link between hTERT/telomerase regulation and p53 status exists in colorectal carcinogenesis, we analysed 43 cases of colorectal carcinoma for hTERT mRNA expression and telomerase activity
14719074	Moreover, a complete analysis of p53 status was performed
14719074	Alterations of p53 gene were found in 44
14719074	19% of cases and missense point mutations represented a high proportion of p53
14713953	Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway
14713953	Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, and inhibition of forkhead transcription factor FOXO3a by Akt is essential for this growth arrest to occur
14712214	Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence
14712214	Senescence induced by PML in HDFs is characterized by a modest increase in p53 levels and activity, the accumulation of hypophosphorylated Rb and a reduced expression of E2F-dependent genes
14712214	To dissect the p53 and Rb family requirements for PML-induced senescence, we used the oncoproteins E6 and E7 from human papillomavirus type 16
14712214	In addition, these viral oncoproteins blocked the formation of PML bodies and excluded both p53 and Rb from PML bodies
14712214	Expression of dominant-negative p53 alone failed to block PML-induced senescence and expression of E6 only delayed the process
14522900	ING1 represses transcription by direct DNA binding and through effects on p53
14522900	Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 function has not been elucidated
14522900	In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53
14522900	Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity
14522900	In addition, we found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382)
14522900	These findings provide novel evidence that p33(ING1b) represses AFP transcription by at least two mechanisms, one of which includes p53
14522900	The first is by binding to the AT-motif and excluding HNF1 binding while possibly targeting HAT activity to promoter regions, and the second is by increasing the levels of active, acetylated p53 via binding and inhibiting the ability of hSIR2 to deacetylate p53 protein
12960381	Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
12960381	Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways
12960381	Moreover, SIRT1-deficient cells exhibited p53 hyperacetylation after DNA damage and increased ionizing radiation-induced thymocyte apoptosis
12960381	In SIRT1-deficient embryonic fibroblasts, however, p53 hyperacetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity
12960381	Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes
12912919	Reversal of human cellular senescence: roles of the p53 and p16 pathways
12912919	Replicative senescence is thought to suppress tumorigenesis by establishing an essentially irreversible growth arrest that requires activities of the p53 and pRB tumor suppressor proteins
12912919	However, cells with low levels of p16 at senescence resumed robust growth upon p53 inactivation, and limited growth upon expression of oncogenic RAS
12912919	In contrast, cells with high levels of p16 at senescence failed to proliferate upon p53 inactivation or RAS expression, although they re-entered the cell cycle without growth after pRB inactivation
12912919	Our results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53
12836417	In fibroblasts, senescence is induced by telomere attrition and depends on p53 and pRb pathways triggered by one or a few critically short telomeres
12835295	The most widely expressed ING1 isoform is p33(ING1b), which can modulate p53, a molecule that is frequently altered in breast cancer
12835295	Reduced ING1 mRNA expression has been observed in primary breast cancer expressing wild-type p53
12835295	METHODS: p33(ING1b), p53, oestrogen receptor (ER), and progesterone receptor (PgR) expression was studied in 86 primary invasive breast cancers using immunohistochemistry
12835295	However, larger tumours were more frequently p53 negative
12835295	CONCLUSIONS: Optimum function of p53 is dependent on p33(ING1b) so that a reduction of nuclear p33(ING1b) expression, as seen in this series, would be predicted to compromise p53 function
12759390	Expression of p53 and p21, which are associated with fibroblast senescence, was assessed by immunoblotting
12759390	Interference with p53 function by transfer of human papillomavirus 16-E6 further extended the lifespan of p16-deficient melanocytes
12756294	The expression of E2 in HPV-positive cancer cells results in the repression of the viral E6/E7 oncogenes, activation of the p53 and pRB pathways, and a G1 cell cycle arrest, followed by induction of cellular senescence
12735636	Expression of p53 in normal sun-exposed and protected skin (type IV-V) in different decades of age
12735636	The checkpoint protein p53, which is activated by DNA damage, is involved in the decision whether the cells should stop replication and proceed to repair their DNA or die by apoptosis
12735636	We evaluate the expression of p53 and the number of apoptotic cells in normal sun-exposed (face) and protected (abdomen) skin in Egyptians between 6 and 77 years of age
12735636	The degree of p53 expression in facial skin significantly increases from a score of 1
12735636	However, p53 expression versus age is significantly higher in the facial skin of older age groups in both males (p = 0
12735636	The expression of wild-type p53 in type IV-V skin therefore correlates with both site and age of the individual
12735636	Increased age-associated expression of p53 in sun-exposed skin, but not in protected areas of skin, is found to reflect an accumulation of the wild-type protein, as judged by the staining pattern
12730243	Moreover, DNA synthesis and the re-entry of senescent cells into cell cycle were resumed upon epidermal growth factor stimulation concomitantly with decreases in p53 and p21
12729792	The bypass of the growth arrest and the acquisition of long-term growth properties could be explained by the loss of p16(INK4a) expression, the ARF/p53 pathway not being altered
12706118	Mutant p53 can delay growth arrest and loss of CDK2 activity in senescing human fibroblasts without reducing p21(WAF1) expression
12706118	Functional wild-type p53 is required for human diploid fibroblasts (HDF) to enter an irreversible growth arrest known as replicative senescence
12706118	Experimentally, abrogation of p53 function by expression of human papillomavirus type 16 E6 or disruption of a key downstream effector p21 by homologous recombination both extended HDF life span
12706118	However, although sufficient to extend life span, p21 down-regulation is not necessary, because expression of a dominant-negative mutant p53 (143(ala)) extends life span without apparently decreasing p21 expression
12706118	Given the importance of p53 in cellular senescence and the general assumption that p21 may be the sole mediator of its action in this process, we have investigated how abrogation of p53 function can overcome senescence without lowering expression of p21
12706118	We have found up-regulated levels of the cyclin-dependent kinase 2 (cdk2) protein in HDF expressing 143(ala) mutant p53 as compared to senescent controls, together with an increase in p21-free cdk2 which, in conjunction with cyclin E, is able to form an active kinase which can phosphorylate the retinoblastoma protein
12668979	Cyclin G1 is a transcriptional target of the tumor suppressor p53, and its expression is increased after DNA damage
12668979	Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A
12668979	However, we found that the p53 levels in the cyclin G1-deficient mice are 2-fold higher that in wild-type mice
12668979	Taken with recent published data, our results suggest that cyclin G1, together with Mdm2, constitute a part of a negative feedback system that attenuates the activity of p53
12668979	In conclusion, our data suggest that the decreased tumor susceptibility after loss of cyclin G1 function is caused by the increased tumor suppressor action of p53
12648672	Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation
12648672	The p53 tumor suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress
12648672	Tight regulation of p53 activation is imperative for preventing tumorigenesis and maintaining normal cell growth; p53 stabilization and transcriptional activation are crucial early events in a cell's battle against genotoxic stress
12648672	Ubiquitination, phosphorylation and acetylation are post-translational modifications to p53 that affect its overall appearance and activity
12648672	Recent findings suggest that these modifications have a profound affect on p53 stability and function
12648672	Defining the precise roles of these modifications in p53 function may show not only that they are markers of the stress response but also that they serve as the focal point in the regulation of p53
12632102	Telomeric repeat-length alterations in colorectal carcinoma are associated with loss of heterozygosity and point mutation in p53 gene
12632102	To investigate whether the two-stage mechanism of cellular aging and immortalization in vitro is involved in the carcinogenesis and immortalization of human colorectal carcinomas, we examined for genetic alterations in the telomeres and in the p53, Rb, and K-ras genes
12632102	Telomeric repeat-lengths (TRL) were measured by Southern blot analysis, and p53 Rb and K-ras gene variants were detected by PCR based assays
12632102	8%) cases, while mutations of the p53 gene were observed in 15 of 36 (41
12632102	7%) cases and LOH involving p53 observed in 14 of 36 (38
12632102	Twelve of 15 (80%) cases with p53 mutations also showed altered TRL, so that p53 mutations were positively associated with TRL alterations (p=0
12632102	4%) cases with LOH of p53 also showed alteration in TRL, also revealing a positive association with TRL (p=0
12632102	The six cases with both p53 mutation and LOH all showed altered TRL
12632102	These results suggest that inactivation of p53 is one of the factors that promotes immortalization and overcomes M1 in colorectal carcinoma
12629205	Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence
12629205	However, the regulation of p53 itself has not been defined
12629205	EGR1-null mouse embryo fibroblasts (MEFs) exhibit decreased expression of p53, p21(Cip1/Waf1), and other p53 "marker" proteins
12629205	WT MEFs that emerge from crisis exhibit a mutated p53 (sequence confirmed), colony formation, and tumorigenicity
12629205	In contrast, high-passage EGR1-null MEFs retain the WT p53 sequence but with much reduced expression, remain untransformed, and grow continuously
12629205	An EGR1-expressing retrovirus restores p53 expression and sencescence to EGR1-null but not p53-null MEFs or postcrisis WT cells
12629205	Taken together, the results establish EGR1 as a major regulator of cell senescence and previously undescribed upstream "gatekeeper" of the p53 tumor suppressor pathway
12615976	The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier M(int) is also a telomere-induced event, although it appears to be independent of p53
12533509	Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform
12533509	Haploid loss of p53 overcame embryonic senescence but failed to prevent the adult mutant mice from prematurely aging, which included decreased life span, reduced body fat deposition, osteoporosis, skin atrophy, and decreased wound healing
12533509	We further demonstrate that mutant cells that escaped senescence had undergone clonal selection for faster proliferation and extensive genetic/molecular alterations, including overexpression of cyclin D1 and cyclin A and loss of p53
12513117	No mutations in the coding regions of the p53 complementary deoxyribonucleic acid were detected in the late-passaged cells
12494881	Another critical factor in the relationship between aging and cancer is p53 function; its activity level is apparently finely tuned to suppress cancer while regulating both apoptosis and the replacement of damaged cells through stem cell proliferation
12494881	The deacetylase activity of the sir2 gene product plays a role in longevity regulation in invertebrates, and also regulates p53 function in mammals, implying yet another link between aging and cancer in mammals
12488624	This concept of senescence is based on our discovery that cells engineered to conditionally express the well-recognized tumor suppressor protein and senescence factor, p53, exhibit asymmetric cell kinetics
12464677	Furthermore, p21, but not p53, was required for inhibition of proliferation by LY
12464677	The lack of p53 involvement suggests that LY does not induce DNA damage
12414954	At the molecular level, cells infected by HCMV, beside the accumulation of large amounts of the cell cycle regulators p53 and pRb, the latter in its hyperphosphorylated form, display a strong induction of the cyclin-dependent kinase inhibitor (cdki) p16(INK4a), a direct effector of the senescence phenotype in fibroblasts, and a decrease of the cdki p21(CIP1/WAF)
12414954	Altogether our results demonstrate for the first time that HCMV, after arresting the cell cycle and inhibiting apoptosis, triggers the cellular senescence program, probably through the p16(INK4a) and p53 pathways
12414655	The tumor suppressor genes p16(INK4A), pRb, and p53 have been implicated in the induction of cellular senescence
12391682	Although it was thought generally that G1 arrest by p53 activation after ionizing radiation was a transient phenomenon to facilitate DNA repair, we found that it is irreversible and permanent in both normal human cells and tumor cells
12362892	When a cell ages, senescing signals arise, typically through DNA damage due to oxidative stress or telomere shortening, and are transduced to proteins such as p53, retinoblastoma protein, and phosphatidylinositol 3-kinase
12220851	Human Sir2 and the 'silencing' of p53 activity
12220851	SIRT1 specifically associates with the p53 tumor suppressor protein and deacetylates it, resulting in negative regulation of p53-mediated transcriptional activation
12220851	Importantly, p53 deacetylation by SIRT1 also prevents cellular senescence and apoptosis induced by DNA damage and stress
12154053	Cotransfection of p33(ING1b) and the tumor suppressor p53 increased the percentage of apoptotic cells yielded by either of these two proteins alone, in agreement with data from tumor cell models
12134086	We have previously demonstrated that overexpression of caveolin-1 arrests mouse embryonic fibroblasts in the G(0)/G(1) phase of the cell cycle through activation of a p53/p21-dependent pathway, indicating a role of caveolin-1 in mediating growth arrest
12111716	Heterozygotic mice carrying a p53 mutation that apparently enhances the stability of the wild-type protein showed shorter lifespans and faster ageing while also developing fewer tumours
12101184	Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction
12101184	Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in beta-galactosidase, a marker of senescence
12101184	Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents
12101184	To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening
12099687	Somatic mutations in the p53 gene account for the extension of replicative life span of macaque cells
12099687	To identify the underlying molecular bases that enable macaque cells to extend their replicative life span (RLS), somatic mutations in p53 were studied in two Japanese macaque (Macaca fuscata) and one long-tailed macaque (Macaca fascicularis) cell strains with extended RLS
12099687	Nucleotide sequences of the p53 whole coding region of each species were determined in early passaged cells and somatic mutations were studied in cells with extended RLS
12099687	Different type of genomic alteration which may disrupt normal p53 function was observed in each strain: (1) introduction of a premature stop codon in one chromosome and loss of heterozygosity for the other; (2) introduction of a missense mutation into each chromosome independently; (3) generation of a novel splice donor site to delete four amino acid residues in the presence of silencing of the normal p53 gene
12097237	Cellular responses to metabolic stress or genomic damage through p53 and related pathways that block cell cycle progression are also altered during oral carcinogenesis
12091906	We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO
12091906	Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias
12089067	In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated beta-galactosidase activity, apoptotic rate, and p53 and p14(AFR) expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity
12051701	Fibroblasts treated with pyruvate undergo a rapid growth arrest accompanied by elevated levels of the cell-cycle regulatory molecules p53, p21, and p16
12015983	A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy
12015983	We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a)
12015983	Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo
12015983	Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage
12006491	Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence
12006491	SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation
12006491	Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation
12006491	When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence
12006491	Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence
11971980	Oncogenic ras and p53 cooperate to induce cellular senescence
11971980	To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products
11971980	Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence
11971980	In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence
11971980	Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence
11971980	Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence
11971980	Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms
11880381	A role for p53 in maintaining and establishing the quiescence growth arrest in human cells
11880381	The p53 tumor suppressor protein induces transient growth arrest or apoptosis in response to genotoxic stress and mediates the irreversible growth arrest of cellular senescence
11880381	We present evidence here that p53 also contributes to the reversible, growth factor-dependent arrest of quiescence (G(0))
11880381	Microinjection of expression vectors encoding either MDM2 or a pRb-binding mutant of SV40 T antigen, both of which abrogate p53 function, stimulated quiescent normal human fibroblasts to initiate DNA synthesis and were 40-70% as effective as wild-type T antigen
11880381	Electrophoretic mobility shift and p53 transactivation assays showed that p53 activity was higher in quiescent and senescent cells compared with proliferating cells
11880381	As proliferating cells entered G(0) after growth factor withdrawal, the p53 mRNA level increased, followed by transient accumulation of the protein
11880381	Shortly thereafter, the expression (mRNA and protein) of p21, a p53 target gene and effector of cell cycle arrest, increased
11880381	Finally, stable expression of the HPV16 E6 oncogene or dominant negative p53 peptide, GSE-22, both of which inhibit p53 function, delayed entry into quiescence following growth factor withdrawal
11880381	Our data indicate that p53 is activated during both quiescence and senescence
11880381	They further suggest that p53 activity contributes, albeit not exclusively, to the quiescent growth arrest
11857402	P53: an ubiquitous target of anticancer drugs
11857402	The p53 tumor suppressor can induce growth arrest, apoptosis and cell senescence
11857402	Not surprisingly, p53 is an appealing target for therapeutic intervention
11857402	Although current anticancer agents do not directly interact with p53, these agents (including DNA damaging drugs, antimetabolites, microtubule-active drugs and inhibitors of the proteasome) cause accumulation of wt p53
11857402	Depending on the p53 status of cancer cells, diverse therapeutic strategies are under development
11857402	These include pharmacological rescue of mutant p53 function and reactivation of wt p53 in E6-expressing cells
11857402	For protection of normal cells, strategies range from abrogation of wt p53 induction, thereby decreasing the toxicity of DNA damaging agents, to activation of wt p53-dependent checkpoints, thereby protecting cells against cell cycle-dependent therapeutics
11850815	P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit
11850815	Direct binding of DeltaNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells
11850815	In contrast p63alpha isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells
11830522	It remains unclear why patients with germ-line p53 mutations (i
11830522	Furthermore, the precise relationship between germ-line p53 mutations and the response to chronic bacterial infections (such as Helicobacter spp
11830522	To assess the role of germ-line p53 deletions in modulating the progression to gastric cancer, p53(+/-) and wild-type (WT) C57BL/6 mice were infected with H
11830522	Nonparametric statistical analysis was performed to determine the effects of p53(+/-), infection status, and postinoculation (p
11830522	There was a significant, protective effect on the development of preneoplastic fundic lesions and invasive carcinoma attributable to the deletion of one p53 allele (P < 0
11830522	None of these lesions were observed in 33 p53(+/-) mice, infected or not, at any time p
11830522	In contrast, IgG2a levels of the p53(+/-) mice were 50-60% lower than those of the WT mice at each time point (P range, <0
11830522	Our results support the hypothesis that germ-line deletion of one p53 allele results in a down-regulated Th1 response to gastric helicobacter infection, possibly because of T-cell senescence, which may indirectly protect against the development of gastric cancer and other epithelial-derived neoplasms associated with chronic inflammation
11795494	SV40 large T antigen, a viral oncoprotein, is known to immortalize human diploid fibroblast by soaking up cellular RB and p53, but its frequency is extremely low
11781834	We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence
11781834	Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells
11781307	Contribution of estrogen receptor alpha to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway
11781307	An oncogenic K-Ras 4B mutant significantly increased MDM2 proteins coprecipitated with p53, and suppressed p53 transcriptional activity
11781307	In turn, DNER exerted its function to decrease MDM2 proteins coprecipitated with p53, followed by the stimulation of p53 activity in the presence of the oncogenic K-Ras 4B mutant
11781307	In addition, overexpression of wild type ERalpha in NIH3T3 cells resulted in the significant increase in the MDM2 protein level and the resultant suppression of p53 transcriptional activity
11781307	The data imply that the ERalpha-AP1 pathway activated by oncogenic K-Ras 4B mutant contributes to the NIH3T3 cells' transformation by modulating p53 transcriptional activity through MDM2
11752408	Induction of most growth inhibitors was delayed but not abolished in cells with homozygous knockout of p53, in agreement with only limited p53 dependence of drug-induced terminal growth arrest
11752408	About one-third of the genes up-regulated in senescent cells and almost all of the down-regulated genes showed decreased or delayed changes in p21(Waf1/Cip1/Sdi1)-deficient cells, indicating that p21 is a major mediator of the effects of p53 on gene expression
11714633	Repression of the human papillomavirus (HPV) type 18 E6/E7 genes in HeLa cells by the bovine papillomavirus E2 transcriptional regulatory protein results in reactivation of the dormant p53 and p105(Rb) tumor suppressor pathways in these cells, repression of telomerase, and profound growth arrest
11707927	Recent studies have shown that senescence can also be induced independently of a PD level by various factors; this premature senescence also appears to involve the activity of p53 and/or p16INK4
11672523	DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis
11672523	Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53
11668507	NaB was effective even in the cancer cells with mutant p53 and/or Rb genes by eliciting cell senescence
11568971	On the other hand, primary normal and HT cells and most cell lines showed constitutively elevated expression of p53/p21(Waf1/Cip1), with a further increment after ultraviolet ir-radiation, indicating a functionally normal p53 pathway
11479224	We found previously that in p53-proficient human glioma cells, TMZ-induced futile DNA MMR resulted not in apoptosis but rather in prolonged, p53- and p21-associated G(2)-M arrest and senescence
11479224	Furthermore, inhibition of the cytoprotective G(2) arrest pathway sensitizes cells to TMZ-induced cytotoxicity and may represent a novel, mechanism-based means of increasing TMZ efficacy in both p53 wild-type and p53 mutant glioma cells
11431323	Using this model, we show that expression of human telomerase catalytic component (hTERT), but not E7-mediated inactivation of pRb or E6/E7-mediated inactivation of p53/pRb, was sufficient to initiate the tumorigenic process by circumventing cellular senescence in astrocytes
11431323	These alterations together, however, cooperated with ras pathway activation (initiated by expression of mutant H-Ras), but not with phosphatidylinositol 3-kinase pathway activation (initiated by expression of myristoylated Akt) or epidermal growth factor receptor activation, to allow for the formation of intracranial tumors strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated human grade III anaplastic astrocytomas
11407594	The unique INK4A/ARF locus at chromosome 9p21 encodes two distinct proteins that intimately link the pRB and p53 tumour suppressor pathways
11389930	It appears that the increased levels of ROS induced DNA damage in the T cells is not the major trigger of apoptosis, via the p53/p21 pathway
11358493	Regulation of cellular senescence by p53
11358493	At the heart of this regulation is p53
11358493	Despite the well-documented central role for p53 in the senescence response, many questions remain regarding how p53 senses senescence-inducing stimuli and how it elicits the senescent phenotype
11349961	Normal somatic cells terminate their replicative life span through a pathway leading to cellular senescence, which is triggered by activation of p53 and/or pRb in response to critically shortened telomere DNA
11238892	Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53
11238892	The cellular function of p53 is complex
11238892	It is well known that p53 plays a key role in cellular response to DNA damage
11238892	Moreover, p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells
11238892	Furthermore, we found that old cells were unable to stabilize p53 in response to DNA damage
11238892	Exogenous expression or stabilization of p53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis
11238892	Our results suggest that stabilization of p53 in response to DNA damage is impaired in old fibroblasts, resulting in induction of necrosis
11213969	Polymerase chain reaction-single-strand conformational polymorphism analysis revealed that TM-31 cells harbor a p53 point mutation in exon 7, codon 238
11157165	The cells maintain high telomerase activity and p53- and Rb-dependent cell cycle checkpoint responses, and serum or genotoxic drugs induce them to acquire a senescence-like phenotype
10752943	Relationship of telomeres and p53 in aging bovine corneal endothelial cell cultures
10752943	PURPOSE: To demonstrate a relationship between telomere lengths and levels of p53 in cultured bovine corneal endothelial cells (CECs) during aging
10752943	Protein p53 was determined using an enzyme-linked immunosorbent sandwich assay
10752943	The p53 levels in bovine CECs were initially small (approximately 60 pg/million cells), but rose 3
10752943	CONCLUSIONS: The data indicate an inverse relationship between telomere lengths (decreasing) and levels of p53 (increasing) in bovine CECs during aging
11063935	The role of telomere maintenance in immortalization and the roles of p16(INK4A), p19(ARF), p53 and other genes in senescence are being further elucidated
10978678	In addition, we determined the levels of cyclin-dependent kinase inhibitors, p21(Waf1) and p16(INK4a), and the p53 tumor suppressor in order to monitor its effect on cell cycle and stress responses
10978678	We observed a great induction of both p53 and p21(Waf1), but not of p16(INK4a) in the premature senescent cells
10978678	These results suggest that a chronic hydroxyurea treatment induces the cellular senescence in association with the induction of p53 and p21(Waf1)
10958672	To determine the physiological and molecular events that specifically require p21, we studied senescence in human diploid fibroblasts expressing the human papillomavirus type 16 E6 oncogene, which confers low p21 levels via enhanced p53 degradation
10911952	By inducing premature senescence with a pulse treatment of H2O2, we can study the role of the cell cycle checkpoint proteins p53, p21, p16 and Rb in gaining each feature of senescence
10911952	Although p53 and Rb control G1 arrest and Rb appears to control cell enlargement, activation of the senescent associate beta-galactosidase, loss of cell replication and multiple molecular changes observed in premature senescent or replicative senescent cells are likely controlled by mechanisms beyond the cell cycle checkpoints
10910364	PML regulates p53 acetylation and premature senescence induced by oncogenic Ras
10910364	The mechanism of p53 activation by oncogenes remains largely unknown
10910364	Here we report that the tumour suppressor PML regulates the p53 response to oncogenic signals
10910364	Lastly, Ras-induced p53 acetylation, p53-CBP complex stabilization and senescence are lost in PML-/- fibroblasts
10910364	Our data establish a link between PML and p53 and indicate that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression
10906511	These results indicate that the higher proliferative activity in prolapsus fibroblasts may result from the decreased expression of p53 protein and may lead to a decrease in the synthesis and deposition of extracellular matrix components
10832053	In this review, we describe three senescence-inducing pathways involving these inhibitors, namely, the p16(INK4a)/Rb pathway, the p19(ARF)/p53/p21(Cip1) pathway, and the PTEN/p27(Kip1) pathway
10767578	Because studies support the involvement of ECM components, TGF-beta and p53 in tumor suppressing mechanisms, our data supports the hypothesis that cellular senescence and upregulation of ECM proteins may be associated with tumor preventive functions
10764661	Using an in vitro model of a conditionally immortalized cell line, we have investigated how human vascular smooth muscle cells (VSMCs) are affected by the expression of simian virus 40 (SV40) large T antigen (LT antigen), which binds to cell cycle regulators such as the tumor suppressor protein p53
10764661	Under permissive-temperature conditions (36 degrees C), the increased rate of cell proliferation was shown to be associated with expression of LT antigen and with LT antigen binding to and inactivation of p53
10739678	Gene-specific repair was analyzed during cellular aging in the dihydrofolate reductase housekeeping gene, the p53 tumor suppressor gene, and the inactive region X(754)
10732786	Activation of p53 by oncogenes
10732786	In non-immortal cells, the adenovirus E1A oncogene activates p53 to promote apoptosis, whereas oncogenic ras activates p53 to promote cellular senescence
10732786	Inactivation of p53 prevents E1A-induced apoptosis or Ras-induced senescence, allowing proliferation to continue unabated
10732786	In each instance, the ability of the oncogene to activate p53 involves the same functions as are required for their transforming potential, implying that p53 activation acts as a fail-safe mechanism to counter hyperproliferative signals
10732786	Furthermore, p19(ARF) is strictly required for oncogene signalling to p53
10732786	The fact that ARF--itself a tumour suppressor--acts as an intermediary in this response argues that the tumour suppressor activity of p53 can arise from its ability to eliminate oncogene-expressing cells
10726978	The p53 protein is able to detect mutation-bearing DNA fragments and is thus indispensable for the UV-induced apoptosis in the epidermis
10726978	Since age is a risk factor for the development of skin tumors we investigated whether ultraviolet induces apoptosis and p53 activation in senescent keratinocytes
10726978	Cultured senescent keratinocytes were irradiated with broad-band ultraviolet, apoptosis was assessed using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) technique and the p53 activation pattern was determined with Western blotting and immunofluorescent staining with a panel of anti-p53 antibodies recognising different conformational forms of the protein (PAb 122, PAb 240, DO-7)
10726978	In senescent keratinocytes arrested in the G1 phase of cell cycle, ultraviolet irradiation (100-2000 J/m2) caused accumulation and nuclear translocation of p53
10726978	There were subtle differences in the p53 activation pattern between senescent keratinocytes and known patterns in young keratinocytes and other cell types
10726978	In senescent keratinocytes a constitutional nuclear expression of p53 (conformational form recognized by PAb 240) was present and the p53 induction in response to ultraviolet radiation was rapid
10712385	Using an in vitro model of a conditionally immortalized cell line, we investigated how human vascular smooth muscle cells (VSMCs) are affected by the expression of simian virus 40 (SV40) large T antigen (LT antigen), which binds to cell cycle regulators, such as the tumor suppressor protein p53
10712385	Under permissive temperature conditions (36 degrees C), the increased rate of cell proliferation was shown to be associated with expression of LT antigen and with LT-antigen binding to and inactivation of p53
10648922	One induces irreversible cell cycle exit involving activation of two tumorsuppressor genes, p53 and pRb, and the proper time point is indicated by a critical shortening of chromosomal ends due to the end-replication problem of DNA synthesis
10629547	Nuclear p53 protein accumulation was found in 60 per cent of the carcinomas, with significant differences in staining characteristics between the Lauren types in the absence of detectable MDM2 protein ( p< 0
10629547	In view of p53/MDM2 homeostasis, the differences in p53 staining characteristics between intestinal and diffuse-type carcinomas probably result, at least in part, from a difference in the prevalence of p53 gene mutations
10593857	Several proto-oncogenes and tumor suppressor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A
10578056	Human cell lines lacking functional p21(wafl/sdi-1), p16(ink4a), or p53 behaved similarly
10578056	The protein levels of p16(ink4a) and p53 did not change uniformly, while the level of p21(wafl/sdi-1) was increased by varying degrees in positive cell lines
10537318	Moreover, in senescent cells in which p53 function was inhibited, DNA synthesis was reinitiated, an effect likely attributable, in part, to the dependence of p21 expression on p53
10467350	To examine if the p21sdi1 gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status
10449031	The cell models studied include SiHa (uterine cervical carcinoma cells expressing E6 and E7 oncoproteins of human papillomavirus type 16) with a transferred chromosome 2, CC1 (choriocarcinoma cells expressing an amino-terminally truncated p53 protein) with a transferred chromosome 7, and JTC-32 (bladder carcinoma cells) with a transferred chromosome 11
10353608	The CDK inhibitor p21waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or differentiation
10353608	The effect of p21waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied
10353608	These results are relevant to treatment of cancer when p53 is inactive
10341711	This appears to trigger growth inhibition via activation of the tumour suppressor gene (TSG) product, p53, and the consequent up-regulation of the cell-cycle inhibitor p21WAF1
10094825	These results support a key role for pRb in the acquisition and maintenance of the differentiated state in human skeletal muscle and, in cooperation with p53, in the control of proliferative capacity and response to external growth factors
10082130	Possible involvement of p21 but not of p16 or p53 in keratinocyte senescence
10082130	It has been reported that p21, p53, and p16 affect the cell cycle and cell senescence
10082130	To investigate the roles of p21, p53, and p16 in the cellular senescence of the cultured keratinocytes, we quantitatively analyzed p21, p53, and p16 levels of keratinocyte strains with different life spans by Western blot with Fluorol mager
10082130	There were no apparent differences in p53 levels between senescent and nonsenescent cells
10082130	In conclusion, p21 but not p16 or p53 may play roles in keratinocyte senescence
10022922	Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53
9916803	In addition, co-expression of telomerase, the viral oncoproteins HPV16 E6/E7 (which inactivate p53 and pRB) and oncogenic HRAS does not result in growth in soft agar
9788435	Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs
9788435	The p53-null human lung cancer cell line H1299 was used in order to generate clones with ecdysone-inducible p53 as well as ecdysone-inducible p21waf1
9788435	Induced expression of p53 resulted in irreversible cell growth arrest with characteristics of replicative senescence, suggesting that p53 can prevent immortalization by activating a senescence program
9788435	The effect of induced p53 and p21waf1 expression on the cytotoxic action of the anti-cancer drugs etoposide and cisplatin was also analysed
9788435	Whereas p21waf1 overexpression conferred increased resistance to killing by either drug, p53 overexpression enhanced the cytotoxic effect of cisplatin but protected against etoposide cytotoxicity
9788435	These results imply that the impact of p53 on susceptibility to chemotherapy may depend greatly on the particular drug and type of DNA damage
9774636	Sp1-mediated transcription of the Werner helicase gene is modulated by Rb and p53
9774636	Coexpression of the WRN-Luc plasmids with various dosages of plasmids expressing Rb or p53 in Saos2 cells lacking active Rb and p53 proteins showed that the introduced Rb upregulates WRN promoter activity a maximum of 2
9774636	5-fold, while p53 downregulates it a maximum of 7-fold, both dose dependently
9774636	Consistently, the overexpressed Rb and p53 proteins also affected the endogenous WRN mRNA levels in Saos2 cells, resulting in an increase with Rb and a decrease with p53
9747456	The senescent cell-derived inhibitor (sdi)-1 (p21) protein has been identified as a downstream mediator of the tumor suppressor p53 in the cell cycle regulation
9732058	At the cellular level, genetic and behavioral differences between aging and photoaging are illustrated with particular emphasis on changes in the structure and function of the tumor suppressor gene p53
9626480	Telomerase activity of sarcoma cell lines and fibroblasts is independent of p53 status
9626480	The p53 gene has been implicated as a crucial barrier to unlimited cell proliferation, and its absence has been shown to allow direct immortalization of cells by certain oncogenes
9626480	The p53 gene may have an additional function of signaling cell growth arrest in response to telomere shortening, which occurs with repeated cellular divisions and ultimately threatens chromosomal stability
9626480	This prompted us to consider whether the enzyme telomerase, responsible for adding new telomeres to chromosomal ends, may be affected by the p53 status of normal and malignant cells
9626480	We investigated whether a relationship between telomerase and p53 could be demonstrated in a human sarcoma cell line containing a missense p53 mutation and several stable transfectants that express the wild-type p53 gene or a temperature-sensitive mutant of p53
9626480	All cell lines had readily detectable telomerase activity regardless of p53 status
9626480	In addition, murine fibroblast cell strains established from tissues of p53+/+ and p53-/- (p53 knockout) mice expressed telomerase regardless of the p53 status of their tissue of origin
9626480	Levels of telomerase subunit mRNA (hEST2) were comparable among cell lines and tissues with different p53 status
9626480	These results imply that p53 status is not associated with telomerase activity per se and that activation of telomerase can occur either in cells completely devoid of p53 or in cells that have functional p53
9546379	We have therefore determined whether these stable growth properties of plaque VSMCs reflect altered activity of RB and/or p53
9546379	Cells were stably transfected with retrovirus constructs that inhibited RB or p53 alone or in combination
9546379	Suppression of p53 and RB together had similar effects but, additionally, resulted in immortalization of normal VSMC cultures
9546379	In contrast, inhibition of RB binding to E2F or ectopic expression of E2F-1 in plaque VSMCs induced massive apoptosis, which required suppression of p53 to rescue cells
9546379	Suppression of RB and p53 together increased cell proliferation and delayed senescence but failed to immortalize plaque VSMCs
9546379	Inhibition of p53 alone had minimal effects on plaque VSMCs but increased the lifespan of normal VSMCs
9546379	Furthermore, both disruption of RB/E2F and inhibition of p53 are required for plaque VSMCs to proliferate without apoptosis
9528853	It depends on the growth regulator p53 and a protein p53 induces, the cyclin dependent kinase inhibitor, p21
9528853	We show here that following DNA damage in mortal fibroblasts, the induction of p21 and p53 is to a large degree shortlived
9528853	By 8 days after a brief exposure to DNA strand breaking agents, bleomycin or actinomycin D, p53 protein is at baseline levels, while the p53 transactivation level is only slightly above its baseline
9528853	Our findings indicate that these cells are very similar to senescent cells and that they have additional factor(s) beside p21 and p53 that maintain cell cycle arrest
9436977	In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0
9436977	Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0
9488478	In human fibroblasts, growth arrest at the end of the normal proliferative life span (induction of senescence) is dependent on the activity of the tumor suppressor protein p53
9488478	Here we have used microinjection of monoclonal antibodies to the N terminus of p53, PAb1801 and DO-1, to reinvestigate the effect of blocking p53 function in senescent human fibroblasts
9488478	Immunofluorescence analysis showed that expression of the p53-inducible cyclin/kinase inhibitor p21sdi1/WAF1 was greatly diminished by targeting p53 with either PAb1801 or DO-1 but remained high and, moreover, still p53 dependent in cells expressing SV40 T antigen
9488478	As previously observed for induction, the maintenance of fibroblast senescence therefore appears to be critically dependent on functional p53
9488478	We suggest that the previous failure to observe this by using SV40 T-antigen mutants to target p53 was most probably due to incomplete abrogation of p53 function
9486850	The immortal fibroblasts used in this study were derived from two Li-Fraumeni (LF) patients who carry in their germ line one wild-type and one mutant p53 allele
9467855	Critical telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA damage signal leading to activation of p53 protein and limited life-span of human diploid fibroblasts
9467855	We proposed previously that telomere shortening may eventually lead to formation of dicentric chromosomes which on subsequent breakage activate a DNA damage response pathway involving the p53 protein
9467855	Recently we have obtained experimental evidence that the p53 protein is activated posttranslationally in human fibroblasts which undergo telomere shortening and subsequent senescence in culture
9467855	In this paper we also show that the increased activity of p53 protein coincides with formation of dicentric chromosomes and senescence
9467855	Also, we have previously found that an increase in the level of the down stream target of p53 protein, p21WAF1/SD11/C1P1, is dependent on both p53 and p300 proteins
9467855	We have also shown that fibroblasts obtained from individuals with Ataxia Telangiectasia lose telomeric DNA at an accelerated rate, activate p53 protein, and undergo premature senescence in culture
9467855	These results suggest that the ataxia-telangiectasia gene (ATM) and p53 are involved in surveillance and regulation of telomeric DNA
9467855	ATM and p53 sense and relay this signal to the cell cycle leading to senescence
9467719	The Rb and p53 tumor suppressors are examples of growth inhibitors that lose the ability to be regulated and are constantly activated during senescence
9453351	The senescent cell-derived inhibitor (sdi)-1 protein (p21 product) has been identified as a downstream mediator of the tumor suppressor p53 in the regulation of cell cycle progression through a G1 phase checkpoint
9440695	These cellular functions depend largely on the activity of p53, a tumour-suppressor gene that determines the cellular response to various types of stress
9440695	Here we report that the biological effects of ING1 and p53 are interrelated and require the activity of both genes: neither of the two genes can, on its own, cause growth inhibition when the other one is suppressed
9440695	A physical association between p33ING1 and p53 proteins has been detected by immunoprecipitation
9440695	These results indicate that p33ING1 is a component of the p53 signalling pathway that cooperates with p53 in the negative regulation of cell proliferation by modulating p53-dependent transcriptional activation
9399646	Further studies indicated that telomerase activity, which was assumably essential for an extended proliferative life-span of neoplastic cells, was abrogated or repressed in the tumor cell lines after induction of pRB (but not p53) expression
9312059	ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase
9312059	We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells
9312059	We show that the DNA binding and transcriptional activity of p53 protein increases with cell age in the absence of any marked increase in the level of p53 protein, and that p21(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300
9312059	Moreover, we detected increased specific activity of p53 protein in AT fibroblasts, which exhibit accelerated telomere loss and undergo premature senescence, compared with normal fibroblasts
9312059	We investigated the possibility that poly(ADP-ribose) polymerase is involved in the post-translational activation of p53 protein in aging cells
9312059	We propose that p53 is post-translationally activated not only in response to DNA damage but also in response to the critical shortening of telomeres that occurs during cellular aging
9234386	The expression of p21 as well as p53 detected by western blotting was compatible with the results of immunohistochemistry in most cases examined
9054499	Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
9054499	However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16
9054499	The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence
9054499	Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells
9053853	The acquisition of genome instability in these E7-HUCs did not correlate with TP53 mutation, as all E7-HUCs contained only wildtype TP53
9024633	During the past year, the story of how p53 suppresses carcinogenesis has increased in complexity
9024633	Further insight has been provided into the activation of latent p53, the biochemical mechanisms involved in growth arrest and apoptosis, and the influence of various signals on these cellular effects
9024633	Additionally, roles for p53 have been described in cell senescence, in suppressing teratogenesis, and in processes that may directly contribute to the maintenance of genomic stability
9303062	Although what genes are involved on chromosome 3 remains speculative, p16 (9p21) and p53 (17p13) are inactivated in a high proportion of oral dysplastic lesions and carcinomas
9303062	Loss of cellular senescence and gain of the immortal phenotype is associated with inactivation of p16 and p53
9156811	If shortening of telomeres reaches a certain critical level, it is recognized as DNA damage by the cell's "guardian of the genome", the tumor suppressor p53
9156811	Stabilization of p53 activates the well characterized cell cycle checkpoint at the G1/S phase boundary and blocks the cell cycle irreversibly
9022808	To examine the possible involvement of multiple gene alterations in extended lifespan or immortalization of normal human fibroblasts, normal human fibroblasts (WHE-7 cells) and skin fibroblasts (MDAH 087 cells) derived from a Li-Fraumeni syndrome patient with a mutated p53 allele were periodically irradiated with x rays
9022808	Single-stranded DNA conformation analysis and DNA sequencing revealed that no additional mutations were induced by x-ray irradiation in exons 2-10 of the p53 gene of the immortal cells (LCS-4X2 cells) and that loss of the wild-type p53 gene was necessary but not sufficient for immortalization
9022808	DNA analysis showed that X9 cells had no mutations in exons 2-10 of the p53 gene
9022808	DNA fingerprint analysis with a multi-locus probe detected DNA rearrangements in LCS-4X2 cells and X9 cells, indicating that both cells could have mutations at a gene or genes other than the p53 gene
9022808	Furthermore, we conclude that immortalization of normal human fibroblasts is a multistep process involving loss or inactivation of multiple genes, such as p53 and a gene on chromosome 6
9022808	Loss of a gene on chromosome 6 without p53 alterations extends cellular lifespan without immortalizing the cells
8985343	Furthermore, v-src cooperated with an immortalizing gene, like simian virus 40 large T, polyomavirus large T, E6 and E7 of human papillomavirus, or an activated p53 mutant, to induce anchorage-independent growth of primary cultures but failed to do so with cytoplasmic transforming genes, like v-abl, v-ras, or v-raf, which did not confer indefinite division potential
8997395	Although the tumor suppressor protein, p53, can trans-activate the p21 gene in some cells, increased levels of nuclear p53 protein could be demonstrated only in the cisplatin model of acute renal failure
8997395	High levels of p21 mRNA were induced in kidney of p53 "null" mice, demonstrating that p21 gene activation was through a p53-independent pathway
8950976	Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence
8950976	Wild-type p53 is necessary for the growth arrest of human diploid fibroblasts (HDF) (and many other cell types) at the end of their proliferative lifespan
8950976	Although p53 may actively mediate senescence, possibly in response to telomere erosion, it is however equally possible that it is merely a permissive factor required for response to some other inducer
8950976	To address this question, we have generated stable transfectants of early passage HDF, represented here by clone LacZ21, in which expression of a beta-galactosidase reporter construct reflects p53 transactivation activity
8950976	Furthermore, a dominant-negative p53 mutant (introduced by retroviral transduction) rescued LacZ21 cells from senescence and generated colonies with extended lifespan in which beta-gal expression was totally abolished
8950976	These data, although not excluding the need for other p53 functions, strongly suggest that p53-mediated transactivation of growth regulatory genes is a direct trigger, rather than a permissive factor, for cellular senescence
8840965	These cells inherit one wild-type and one mutant p53 allele and lose the former during culture
8840965	These results indicate that p53 and p21 are not required for replicative senescence in human fibroblasts
8893868	Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease
8799138	Cells reverted to their preimmortalized state, as indicated by changes in growth characteristics and p53 levels, and their fate conformed to the telomere hypothesis of replicative cell senescence
8817002	In this study we determined whether the repression of c-fos at M1 was downstream of the p53 or pRB-like "arms" of the M1 mechanism
8817002	We examined c-fos expression during the entire lifespan of normal human fibroblasts carrying E6 (which binds p53), E7 (which binds pRB), or both E6 and E7 of human papilloma virus type 16
8817002	These results demonstrate the unique physiology of fibroblasts during the extended lifespan between M1 and M2 and suggest that p53 might participate in the process that represses the c-fos gene at the onset of cellular senescence
8647635	Mutation in p53 and de-regulation of p53-related gene expression in three human cell lines immortalized with 4-nitroquinoline 1-oxide or 60Co gamma rays
8647635	We detected expression of only mutated p53 mRNA by direct sequencing of the reverse-transcribed mRNA in 3 human cell lines immortalized either with 4-nitroquinoline 1-oxide or with 60Co gamma rays
8647635	The expression of sdiI/p21 and mdm2, both of which are positively regulated by wild-type p53, was significantly down-regulated in the immortalized cell lines, resulting in over-expression of cdk2 and cdk4
8647635	These results indicate that the p53 cascade may play an important role in the immortalization of human cells
21544354	The human papillomavirus (HPV) oncoproteins, HPV-16 E6 and E7, can block the progression to senescence in fibroblasts by associations with p53 and pRb, respectively
21544354	In the present report, we show that only wild-type HPV-16 E6 allows complete degradation of p53, immortalization and reactivation of telomerase activity in HME cells
21544354	These results suggest that the ability of HPV-16 wild-type and mutant E6 proteins to degrade p53 in intact HME cells and keratinocytes does not completely correlate with their ability to degrade p53 in a cell-free system
21544354	This discrepancy between in vitro and in vivo p53 degradation may be biologically significant and may provide insight into the susceptibility of certain human cells and tissues for reactivation of telomerase and immortalization
8632215	Furthermore, Bax mRNA, an apoptosis-inducer gene, was increased with addition of AMP, suggesting that the induction of apoptosis may be channeled through the p53 pathway
9114431	This review outlines the intrinsic inhibitory signal pathways that link this clock to cell cycle arrest, focussing on the role of tumour suppressor gene products, particularly the p53 and pRb proteins
9109495	Although the precise mechanisms of immortalization are unknown at present, data indicate that the p53 cascade appears to be important for the immortalization of human cells
9109495	The loss of functions of normal p53 may induce genomic instability, resulting in mutations of some other unknown genes that are more directly involved in the immortalization of human cells
8934878	The only genes known to reactivate DNA synthesis in senescent cells are viral oncogenes encoding proteins that bind and inactivate the p53 and retinoblastoma (pRb) tumor suppressor proteins
8706802	The data demonstrate that SDI1 is an important downstream effector of p53, but here we report that it can also cause inhibition of DNA synthesis in several immortal human cell lines, independent of p53 or Rb status
8706800	These effects are mediated through inactivation of function of growth suppressors pRB and p53 via complex formation with T antigen
8706799	From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging
8706799	These breaks activate a p53 dependent or independent DNA-damage pathway that leads to the induction of a family of inhibitors of cyclin dependent kinases (including p21 and p16) and the eventual G1 block of senescence
8706799	In agreement with this hypothesis, we demonstrate that the level of p53 protein increases in near senescent cultures of MDFs
7475551	Cancer progression and p53
7475551	The p53 gene is a "guardian of the genome"--it regulates multiple components of the DNA damage control response and promotes cellular senescence
7475551	Disabling mutations and deletions of p53 occur in 50% of human tumours
7566157	The p21 gene is under the transcriptional control of p53 (ref
21552918	Modulation of proliferation and tumorigenic potential of cervical-carcinoma cells by the expression of sense and antisense p53
21552918	Previous studies from our laboratory demonstrated that overexpression of wild-type p53 suppresses the growth and alters the differentiation pattern of HPV-immortalized keratinocytes (Woodworth et al: Cell Growth Differ 4: 367-376, 1993)
21552918	In the present report we describe the use of sense and antisense p53 retroviral vectors to modulate the expression levels of the p53 tumor suppressor gene in cervical carcinoma cells
21552918	Representative cell lines (C-4 I, ME-180 and C-33 A) were selected for this study on the basis of their various expression levels of either wild-type or mutated p53, and also of their content of integrated human papillomavirus sequences
21552918	Our results show that p53 overexpression from the sense construct decreased the growth rate and tumorigenic potential of the HPV-negative C-4 I cell line, whereas it had no effect on the HPV-positive ME-180 and C-33 A cells
21552918	However, examination of the individual colonies early after transfection with sense constructs by light microscopy showed that overexpression of wild-type p53 in ME-180 induced significant morphological alterations resulting in cellular senescence
21552918	Nevertheless, the p53 overexpressing, ME-180-derived cell line established after selection did not exhibit any major changes compared to the parental cell line
21552918	In the case of C-33 A, the presence of high levels of mutant p53 prevented the exogenous wild-type p53 from causing any significant modulatory action on their proliferation or neoplastic phenotype
7667293	Increased activity of p53 in senescing fibroblasts
7667293	The p53 tumor-suppressor protein binds DNA and activates the expression of a 21-kDa protein that inhibits both the activity of cyclin-dependent kinases and the function of proliferating cell nuclear antigen
7667293	Since p21 expression has been reported to increase 10- to 20-fold as human diploid fibroblasts lose the ability to replicate, we examined the expression and activity of p53 during replicative aging
7667293	Similar levels of total p53 mRNA and protein were expressed in low-passage (young) and high-passage (old) cells but both DNA binding activity in vitro and transcriptional activity of p53 in vivo were increased severalfold in high-passage cells
7667293	While the basis of increased p53 activity is presently unclear, it is not correlated with differential phosphorylation or changes in p53-mouse double minute 2 gene product interactions
7603034	EXPERIMENTAL DESIGN: The effects of 9NC on HepG2 cells were evaluated by monitoring DNA synthesis, morphologic and ultrastructural changes of cells, and perturbation in the cell cycle and by assessing the levels of p53 protein and SDI1 mRNA
7603034	No significant alteration in the p53 protein level was noted in 9NC-treated cells
7538902	Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1
7538902	Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function
7538902	We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector
7538902	Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator
7538902	In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent
7538902	We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent
7564558	Expression of Rb and p53 mRNA after growth factor stimulation was also examined
7564558	Young and old cells had similar Rb mRNA levels, whereas the p53 mRNA level was significantly reduced in old cells
7564558	However, no significant change was found in p53 gene transcriptions after FGF addition
7698234	Increased p53 protein associated with aging in human diploid fibroblasts
7698234	Molecular changes associated with cellular aging in a strain of human diploid fibroblasts, IMR-90, were addressed by analyzing the expression of the tumor suppressor protein, p53
7698234	When p53 was immunoprecipitated by monoclonal antibodies and detected by Western immunoblot analysis, more protein per cell was detected in the near-senescent cultures
7698234	A greater than 10-fold increase in p53 protein was measured with the PAb 1801 (N-terminal-specific) anti-p53 antibody, whereas PAb 122 (C-terminal-specific) measured a 5-fold increase
7698234	Although near-senescent cultures demonstrated a higher level of p53 than young cells, these cultures had similar charges and molecular weight p53 isoforms when analyzed by two-dimensional Western blots
7698234	When p53 RNA was compared to total RNA there was a decrease in p53 RNA with age, but on a per cell basis p53 RNA was elevated
7698234	These results provide evidence for transcriptional regulation of p53 during aging and support the hypothesis that elevated levels of p53 protein may play a role in cellular senescence
7898935	Alterations in telomeric repeat length in lung cancer are associated with loss of heterozygosity in p53 and Rb
7898935	In the two-stage model of controlling cellular senescence in cultured human fibroblasts, retinoblastoma (Rb) and p53 proteins may be key factors regulating the mortality stage 1 mechanism
7898935	Ten of them revealed allelic loss of both p53 and Rb genes, and remaining six showed no abnormalities in both genes
7898935	We propose that inactivation of both p53 and Rb genes may promote cell divisions causing telomere shortening in lung cancer as in the two-stage model, while there may be another pathway to overcome both M1 and M2 mechanisms, especially for adenocarcinoma
7822435	Likewise, the steady state levels of p53, a protein known to be involved in the G1 checkpoint of the cell cycle, were similar in early-passage fibroblasts from normal and WS subjects
7822435	The levels of p53 were not increased in senescent fibroblasts, whether derived from normal or WS subjects
7958891	HPV16 E6 binds p53, leading to rapid degradation of p53, whereas E7 binds and alters pRb and other proteins
7958891	These results implicate p53 loss, but not pRb alteration, in genome destabilization
8208534	Escape from senescence in human diploid fibroblasts induced directly by mutant p53
8208534	To address this question, we used the novel approach of directly assessing the effect of mutant p53 on 'pre-aged' human diploid fibroblasts (HDF), thereby avoiding the uncertainty of additional cooperating events, inherent in transgenic models
8208534	HDF were passaged till near-senescent and then infected with an amphotropic retroviral vector encoding an ala143 human mutant p53
8208534	The results show conclusively that p53 mutation alone is sufficient to extend the proliferative lifespan of normal fibroblasts by approximately 17 population doublings, but has no phenotypic effect on 'young' fibroblasts
8208534	We conclude that a key tumour-limiting function of wild-type p53 is to mediate growth arrest after a given number of cell divisions, in agreement with data implicating a p53-regulated gene, WAF-1/sdi-1, in cellular senescence
7911228	The p53 tumour-suppressor protein controls the expression of a gene encoding the p21 cyclin-dependent protein kinase (CDK) regulator
8262140	Examination of p53 protein in growing, quiescent, and senescent cells revealed no significant differences in levels between the different growth states
8018955	These cells overexpressed p53 protein and had an amplified epidermal growth factor (EGF) receptor gene that resulted in high level expression of tyrosine phosphorylated EGF receptor protein
21573400	In mammary epithelial cells, the M1 mechanism involves de-regulation of p53 whereas in fibroblasts both the retinoblastoma (Rb) and p53 gene products are implicated
8389027	Immortalization is the consequence of the inactivation or bypass of two mortality stage mechanisms, M1 and M2, which are controlled by several genes including Rb and p53 in human fibroblasts
8389027	Fibroblasts expressing both E6 (which binds p53) and E7 (which binds Rb) bypass M1 and continue replicating (exhibit an extended lifespan) until an independent mechanism, M2, is activated
8518411	However, although both p53 and Rb are involved in the M1 mechanism of fibroblast cellular senescence, in human mammary epithelial cells only p53 is involved
8518411	Events which can abrogate p53 functions are described, as is the current state of knowledge about the function of p53
8485202	Alteration of p53 gene in chemically transformed HOS cell lines has recently been shown
1326671	Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes
1326671	The E6 proteins of the high-risk human papillomaviruses (HPVs) have been shown to form a complex with and induce the degradation of human p53 in vitro
1326671	To determine whether p53 is degraded more rapidly in cells expressing E6 in vivo, the half-life of p53 was determined by pulse-chase analysis in early-passage normal human keratinocytes and fibroblasts, human keratinocytes immortalized with HPV type 16 (HPV16) E6 plus E7, and nonimmortal keratinocytes transfected with E6
1326671	The results of these experiments indicate that (i) the half-life of newly synthesized p53 is relatively long (4 h) in early-passage human keratinocytes and fibroblasts but short in keratinocytes expressing E6 (15 to 30 min), (ii) a similar increased rate of p53 degradation was measured in lines immortalized with HPV16 E6 plus E7 and senescent cells expressing E6, indicating that this increase is not simply the result of selection in the immortalized lines, and (iii) very low levels of expression of E6 result in a greatly decreased half-life of p53, suggesting that E6 acts in a catalytic manner
1378532	Cellular and molecular advances in elucidating p53 function
1378532	The finding that in many human tumors there is allelic loss and/or mutations in p53, in combination with recognition that these events may play a role in multi-stage carcinogenesis, has focused considerable interest on this gene
1378532	To help keep abreast of this rapidly expanding field, recent experiments on the role and potential regulation of p53 are described: these include discussions of p53 as an anti-proliferative agent, the p53 mutations found in human tumors and tumor cell lines, the conformational states of p53, phosphorylation of p53 by p34cdc2, and signals for the nuclear localization of p53
1652450	A role for both RB and p53 in the regulation of human cellular senescence
1652450	We present evidence for the possible involvement of both the RB and p53 proteins in the regulation of cellular senescence

Entries Per Page

Displaying Page of

Navigator

1.General information
2.Neighbors in the network
3.Gene Ontology Annotation
4.Expression levels
5.Regulation
6.Text-mining results

HCSGD entry for TP53

1. General information

2. Neighbors in the network

3. Gene ontology annotation

GO ID

GO term

Evidence

Category

4. Expression levels in datasets

Meta-analysis result

Individual experiment result ( "-" represent NA in the specific microarray platform )

( "-" represent NA in the specific microarray platform )

5. Regulation relationships with compounds/drugs/microRNAs

Compounds

Compound

Target

Confidence score

Uniprot

Drugs

Name

Drug

Accession number

MicroRNAs

mirTarBase

MiRNA_name

mirBase ID

miRTarBase ID

Experiment

Support type

References (Pubmed ID)

mirRecord

MicroRNA name

mirBase ID

Target site number

MiRNA mature ID

Test method inter

MiRNA regulation site

Reporter target site

Pubmed ID

6. Text-mining results about the gene

Gene occurances in abstracts of cellular senescence-associated articles: 1061 abstracts the gene occurs.

PubMed ID of the article

Sentenece the gene occurs

Navigator

Individual experiment result
( "-" represent NA in the specific microarray platform )