HCSGD entry for ATM
1. General information
| Official gene symbol | ATM |
|---|---|
| Entrez ID | 472 |
| Gene full name | ataxia telangiectasia mutated |
| Other gene symbols | AT1 ATA ATC ATD ATDC ATE TEL1 TELO1 |
| Links to Entrez Gene | Links to Entrez Gene |
2. Neighbors in the network
3. Gene ontology annotation
GO ID | GO term | Evidence | Category |
|---|---|---|---|
| GO:0000077 | DNA damage checkpoint | IEA | biological_process |
| GO:0000723 | Telomere maintenance | IEA | biological_process |
| GO:0000724 | Double-strand break repair via homologous recombination | TAS | biological_process |
| GO:0000781 | Chromosome, telomeric region | IDA | cellular_component |
| GO:0001666 | Response to hypoxia | IEA | biological_process |
| GO:0001756 | Somitogenesis | IEA | biological_process |
| GO:0002331 | Pre-B cell allelic exclusion | IEA ISS | biological_process |
| GO:0003677 | DNA binding | IEA | molecular_function |
| GO:0004674 | Protein serine/threonine kinase activity | IDA IEA | molecular_function |
| GO:0004677 | DNA-dependent protein kinase activity | IDA | molecular_function |
| GO:0005515 | Protein binding | IPI | molecular_function |
| GO:0005524 | ATP binding | IEA | molecular_function |
| GO:0005634 | Nucleus | IEA | cellular_component |
| GO:0005654 | Nucleoplasm | TAS | cellular_component |
| GO:0005737 | Cytoplasm | IEA | cellular_component |
| GO:0005819 | Spindle | IEA | cellular_component |
| GO:0006281 | DNA repair | IEA TAS | biological_process |
| GO:0006302 | Double-strand break repair | TAS | biological_process |
| GO:0006468 | Protein phosphorylation | IDA | biological_process |
| GO:0006974 | Cellular response to DNA damage stimulus | IMP | biological_process |
| GO:0006975 | DNA damage induced protein phosphorylation | IDA | biological_process |
| GO:0006977 | DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest | TAS | biological_process |
| GO:0007050 | Cell cycle arrest | IMP | biological_process |
| GO:0007094 | Mitotic spindle assembly checkpoint | IMP | biological_process |
| GO:0007131 | Reciprocal meiotic recombination | TAS | biological_process |
| GO:0007165 | Signal transduction | TAS | biological_process |
| GO:0007420 | Brain development | IEA | biological_process |
| GO:0007507 | Heart development | IEA | biological_process |
| GO:0008630 | Intrinsic apoptotic signaling pathway in response to DNA damage | IEA | biological_process |
| GO:0010212 | Response to ionizing radiation | IDA IEA | biological_process |
| GO:0016023 | Cytoplasmic membrane-bounded vesicle | IEA | cellular_component |
| GO:0016303 | 1-phosphatidylinositol-3-kinase activity | IMP | molecular_function |
| GO:0016572 | Histone phosphorylation | IEA | biological_process |
| GO:0018105 | Peptidyl-serine phosphorylation | IDA | biological_process |
| GO:0030889 | Negative regulation of B cell proliferation | IMP | biological_process |
| GO:0032403 | Protein complex binding | IDA | molecular_function |
| GO:0035174 | Histone serine kinase activity | IEA | molecular_function |
| GO:0036092 | Phosphatidylinositol-3-phosphate biosynthetic process | IMP | biological_process |
| GO:0042159 | Lipoprotein catabolic process | IEA | biological_process |
| GO:0043065 | Positive regulation of apoptotic process | IMP | biological_process |
| GO:0043517 | Positive regulation of DNA damage response, signal transduction by p53 class mediator | IMP | biological_process |
| GO:0043525 | Positive regulation of neuron apoptotic process | IEA | biological_process |
| GO:0046777 | Protein autophosphorylation | IDA IEA | biological_process |
| GO:0046854 | Phosphatidylinositol phosphorylation | IMP | biological_process |
| GO:0046983 | Protein dimerization activity | IDA | molecular_function |
| GO:0047485 | Protein N-terminus binding | IDA | molecular_function |
| GO:0048599 | Oocyte development | IEA | biological_process |
| GO:0051402 | Neuron apoptotic process | IEA | biological_process |
| GO:0051726 | Regulation of cell cycle | IEA | biological_process |
| GO:0071044 | Histone mRNA catabolic process | IDA | biological_process |
| GO:0071480 | Cellular response to gamma radiation | IDA | biological_process |
| GO:0072434 | Signal transduction involved in mitotic G2 DNA damage checkpoint | IMP | biological_process |
| GO:0090399 | Replicative senescence | IEA IMP | biological_process |
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4. Expression levels in datasets
- Meta-analysis result
| p-value up | p-value down | FDR up | FDR down |
|---|---|---|---|
| 0.0514567380 | 0.9532557806 | 0.4979385294 | 1.0000000000 |
- Individual experiment result
( "-" represent NA in the specific microarray platform )
( "-" represent NA in the specific microarray platform )
| Data source | Up or down | Log fold change |
|---|---|---|
| GSE11954 | Up | 0.1077040536 |
| GSE13712_SHEAR | Down | -0.0414811526 |
| GSE13712_STATIC | Up | 0.2489677015 |
| GSE19018 | Up | 0.2491128421 |
| GSE19899_A1 | Up | 0.0744366979 |
| GSE19899_A2 | Up | 0.3152199553 |
| PubMed_21979375_A1 | Up | 0.1184861704 |
| PubMed_21979375_A2 | Up | 0.5436180464 |
| GSE35957 | Down | -0.0453642918 |
| GSE36640 | Down | -0.0706587007 |
| GSE54402 | Up | 0.2410150523 |
| GSE9593 | Up | 0.1447276837 |
| GSE43922 | - | - |
| GSE24585 | - | - |
| GSE37065 | - | - |
| GSE28863_A1 | Up | 0.7277902326 |
| GSE28863_A2 | Up | 0.5876125456 |
| GSE28863_A3 | Down | -0.8107158450 |
| GSE28863_A4 | Up | 0.1770469331 |
| GSE48662 | Up | 0.1971677762 |
5. Regulation relationships with compounds/drugs/microRNAs
- Compounds
Not regulated by compounds
- Drugs
Name | Drug | Accession number |
|---|---|---|
- MicroRNAs
- mirTarBase
MiRNA_name | mirBase ID | miRTarBase ID | Experiment | Support type | References (Pubmed ID) |
|---|---|---|---|---|---|
| hsa-miR-421 | MIMAT0003339 | MIRT003215 | Luciferase reporter assay//qRT-PCR//Western blot | Functional MTI | 20080624 |
| hsa-miR-101-5p | MIMAT0004513 | MIRT005559 | Luciferase reporter assay//qRT-PCR | Non-Functional MTI | 20617180 |
| hsa-miR-101-3p | MIMAT0000099 | MIRT005560 | Luciferase reporter assay//qRT-PCR | Functional MTI | 20617180 |
| hsa-miR-374a-5p | MIMAT0000727 | MIRT005573 | Immunoblot//Luciferase reporter assay//qRT-PCR | Functional MTI | 21274007 |
| hsa-miR-181a-5p | MIMAT0000256 | MIRT005576 | Immunoblot//Luciferase reporter assay//qRT-PCR | Functional MTI | 21274007 |
| hsa-miR-100-5p | MIMAT0000098 | MIRT005913 | Luciferase reporter assay//qRT-PCR//Western blot | Functional MTI | 20869334 |
| hsa-miR-18a-5p | MIMAT0000072 | MIRT006118 | Luciferase reporter assay | Functional MTI | 23437304 |
| hsa-miR-18a-5p | MIMAT0000072 | MIRT006118 | Sequencing | Functional MTI (Weak) | 20371350 |
| hsa-miR-19b-3p | MIMAT0000074 | MIRT031122 | Sequencing | Functional MTI (Weak) | 20371350 |
| hsa-miR-92a-3p | MIMAT0000092 | MIRT049505 | CLASH | Functional MTI (Weak) | 23622248 |
| hsa-miR-3144-3p | MIMAT0015015 | MIRT052661 | CLASH | Functional MTI (Weak) | 23622248 |
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- mirRecord
MicroRNA name | mirBase ID | Target site number | MiRNA mature ID | Test method inter | MiRNA regulation site | Reporter target site | Pubmed ID |
|---|---|---|---|---|---|---|---|
| hsa-miR-101-5p | MIMAT0004513 | 1 | hsa-miR-101* | 20617180 | |||
| hsa-miR-101-3p | MIMAT0000099 | 1 | hsa-miR-101 | 20617180 |
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6. Text-mining results about the gene
Gene occurances in abstracts of cellular senescence-associated articles: 101 abstracts the gene occurs.
PubMed ID of the article | Sentenece the gene occurs |
|---|---|
| 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 |
| 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 |
| 26871293 | These effects of As2O3 trigger an extensive DNA damage response at the telomere, which includes up-regulation of ATM, ATR, 53BP1, gamma-H2AX and Mer11, in parallel with telomere fusion and 3'-overhang degradation |
| 26848154 | Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC-1beta-dependent mitochondrial biogenesis, contributing to aROS-mediated activation of the DDR and cell cycle arrest |
| 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 | Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass |
| 26636375 | Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition |
| 26636375 | Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress |
| 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 | The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy |
| 26404840 | GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a) |
| 26340421 | ATM, MacroH2A |
| 26311700 | Ataxia-telangiectasia mutated (ATM) gene could cause ataxia telangiectasia which is an autosomal recessive disease |
| 26311700 | The ATM protein kinase encoded by the ATM gene mainly distributed in nucleus as a master regulator of the DNA damage response and apoptosis via cell signaling pathways |
| 26311700 | The ATM kinase plays a key role in the pathogenesis of cellular senescence and tumor genesis |
| 26311700 | Recently, some studies have indicated that ATM protein kinase is involved in pathological neovascularization, suggesting that it could be a novel potential therapeutic target in diseases associated with pathological angiogenesis |
| 26151554 | This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM) checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence |
| 26151554 | Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation |
| 26151554 | Interestingly, ATM inhibition makes 46BR |
| 26151554 | These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression |
| 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 | ATM couples replication stress and metabolic reprogramming during cellular senescence |
| 25937285 | Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism |
| 25937285 | ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency |
| 25937285 | These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation |
| 25937285 | Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence |
| 25801233 | Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition |
| 25801233 | The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation |
| 25801233 | After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase |
| 25801233 | ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death |
| 25801233 | These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected |
| 25801233 | Formation of gammaH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of gammaH2AX, whereas DNA-PK caused persistence of gammaH2AX |
| 25801233 | Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted |
| 25744025 | The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM) activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing |
| 25744025 | In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, resulted in the loss of ATM from DNA lesions |
| 25744025 | However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruption ablated downstream Chk2 activation and induced genomic instability |
| 25649709 | Surprisingly, in vascular smooth muscle cell (VSMC) activation of DNA damage response pathway downstream of ataxia-telangiectasia mutated (ATM) was observed |
| 25649709 | Thus, we have shown that curcumin can induce senescence of cells building the vasculature, which is DNA damage and ATM independent and is not induced by increased reactive oxygen species (ROS) level |
| 25573782 | RESULTS: We define a discrete, logical model encompassing ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) pathways activation upon DNA damage, as well as G1/S checkpoint main components |
| 25416819 | Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence |
| 25416819 | Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS) |
| 25416819 | Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence |
| 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 |
| 25416819 | Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence |
| 25416819 | By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM |
| 25336634 | Oxidative stress and persistent DNA damage response contribute to cellular senescence, a degeneration process critically involving ataxia telangiectasia-mutated (ATM) and p53 |
| 25336634 | SelH shRNA MRC-5 diploid fibroblasts under ambient O2 displayed a distinct profile of senescence including beta-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation |
| 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 |
| 25119968 | S4 and S3R cells have the same level of p70 nibrin, however p70 from S4 cells was able to form more complexes with ATM and BRCA1 |
| 25093836 | A novel ATM/TP53/p21-mediated checkpoint only activated by chronic gamma-irradiation |
| 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 |
| 25093836 | Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells |
| 24937130 | ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence |
| 24937130 | Recent studies suggest that the ataxia telangiectasia mutant (ATM) kinase is not only a key protein mediating cellular responses to DNA damage, but also regulates cellular senescence induced by telomere end exposure (in RS) or persistent DNA damage (in SIPS) |
| 24937130 | We demonstrate that ATM plays an important role in insulin-like growth factor 1 (IGF-1) expression, that in turn, regulates downstream sCLU induction during senescence |
| 24937130 | Loss of ATM activity, either by genomic mutation (ATM-deficient fibroblasts from an ataxia telangiectasia patient) or by administration of a chemical inhibitor (AAI, an inhibitor of ATM and ATR), blocks IGF-1-sCLU expression in senescent cells |
| 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 | Notably, the increased H2AX phosphorylation levels observed in Ppm1d(-/-) MEFs were primarily associated with S-phase cells and predominantly dependent on the activation of ATM |
| 24052948 | This is promoted by ATM and antagonized by p53 |
| 24023735 | We identify an upregulation of Chk1, ATM and ATR pathways in p53 negative cells and 61 other predictions obtained by knockout tests mimicking mutations |
| 23952478 | On the contrary, ATM inhibitor did not affect the protective effect of morin in UVB irradiation-induced p53 reporter activation |
| 23933816 | ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence |
| 23933816 | The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells |
| 23897750 | Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence |
| 23688655 | The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1) |
| 23649808 | In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM |
| 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 | 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 |
| 23557734 | METHODS: Senescence was assessed by measuring the SA-beta-Galactosidase activity, the expressions of p16(INK4a) and ATM, and cell cycle analysis |
| 23383259 | Studies with mismatch repair mutants and MSH6, Rad51 and ATM knockdowns revealed that autophagy induced by O(6)MeG requires mismatch repair and ATM, and is counteracted by homologous recombination |
| 23363784 | Specifically, persistent activation of ATM and expression of gammaH2AX in untreated cells appears to report constitutive DNA damage induced by endogenous ROS |
| 23341930 | We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of gammaH2AX and 53BP1 |
| 23272087 | Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate epithelial cells |
| 23272087 | The ATM/ATR DNA damage checkpoint functions in the maintenance of genetic stability and some missense variants of the ATM gene have been shown to confer a moderate increased risk of prostate cancer |
| 23272087 | Here, we show that exposure of non-malignant prostate epithelial cells (HPr-1AR) to androgen led to activation of the ATM/ATR DNA damage response and induction of cellular senescence |
| 23272087 | Notably, knockdown of the ATM gene expression in HPr-1AR cells can promote androgen-induced TMPRSS2: ERG rearrangement, a prostate-specific chromosome translocation frequently found in prostate cancer cells |
| 23272087 | Intriguingly, unlike the non-malignant prostate epithelial cells, the ATM/ATR DNA damage checkpoint appears to be defective in prostate cancer cells, since androgen treatment only induced a partial activation of the DNA damage response |
| 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 |
| 23272087 | Our findings demonstrate that ATM/ATR inactivation is a crucial step in promoting androgen-induced genomic instability and prostate carcinogenesis |
| 23180582 | Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-kappaB-related, senescence-associated secretory phenotype (SASP) |
| 23050037 | Foci of phosphorylated histone H2AX and ATM are the surrogate markers of DNA double strand breaks |
| 23050037 | Importantly, large foci of phosphorylated H2AX were always colocalized with phosphorylated ATM foci |
| 22797809 | Pathological neoangiogenesis depends on oxidative stress regulation by ATM |
| 22797809 | The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis |
| 22797809 | Aside from DDR signaling, ATM also functions in oxidative defense |
| 22797809 | Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS) |
| 22797809 | Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina |
| 22797809 | Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade |
| 23552604 | The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage |
| 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 |
| 22170748 | Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer |
| 22067284 | We have shown before that constitutive DNA damage signaling represented by H2AX-Ser139 phosphorylation and ATM activation in untreated normal and tumor cells is a reporter of the persistent DNA replication stress induced by endogenous oxidants, the by-products of aerobic respiration |
| 21864489 | The ATM phosphorylation was documented early after drug exposure, while no telomerase activation was observed |
| 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 |
| 21500551 | Changes after co-incubation with KU55993 (an inhibitor of ATM) were examined with methods mentioned above |
| 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 |
| 21471287 | Accordingly, increased constitutive levels of IFI16 and AIM2 proteins in ataxia telangiectasia mutated (ATM) HDFs were associated with the activation of the IFN signaling and increased levels of IL-1beta |
| 26097382 | Using the ataxia telangiectasia-mutated inhibitor CGK733 to block IRIF formation and the topoisomerase II inhibitor etoposide to prevent IRIF resolution, we obtained a Z' >0 |
| 21336312 | Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction |
| 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 |
| 21228624 | Previously, we demonstrated that ATM kinase can regulate changes in PML NB number in response to DNA double-strand breaks (DSBs) |
| 21228624 | Together these data implicate KAP1-dependent changes in chromatin structure as one possible mechanism by which ATM may regulate PML NB number in response to DNA damage |
| 21037379 | Additionally, depletion of tankyrase 1 resulted in concomitant and rapid reduction of the nonhomologous end-joining protein DNA-PKcs, while Ku86 and ATM protein levels remained unchanged; DNA-PKcs mRNA levels were also unaffected |
| 20939035 | The induction of cyclin dependent kinase inhibitors p21(WAF1) and p27(KIP1) and gammaH2AX and activation of ATM markers of DNA damage response were measured in parallel with DNA/DAPI maximal pixel and nuclear area |
| 20889973 | The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain |
| 20889973 | The DNA damage kinase ATM plays a central role in maintaining genomic stability |
| 20889973 | ATM mutations cause the genetic disorder ataxia telangiectasia, which is primarily characterized by progressive neurodegeneration and cancer susceptibility |
| 20889973 | Although the importance of ATM function to protect against oxidative DNA damage and during aging is well described, the mechanism of ATM activation by these stimuli is not known |
| 20889973 | Here we identify ATM interactor (ATMIN) as an essential component of the ATM signaling pathway in response to oxidative stress and aging |
| 20889973 | In response to acute oxidative stress, atmin(Delta/Delta) mouse embryonic fibroblasts showed slightly lower levels of ATM phosphorylation and reduced ATM substrate phosphorylation |
| 20889973 | Conditional deletion of ATMIN in the murine nervous system (atmin(DeltaN)) resulted in reduced numbers of dopaminergic neurons, as does ATM deficiency |
| 20889973 | ATM activity was observed in old, but not in young, control mice, but aging-induced ATM signaling was impaired by ATMIN deficiency |
| 20889973 | These results suggest that ATMIN mediates ATM activation by oxidative stress, and thereby ATMIN protects the aging brain by preventing accumulation of DNA damage |
| 20639198 | The DNA damage response and its main signaling pathway involving ataxia telangiectasia mutated (ATM) have been implicated in playing a central role in mediating the actions of oxidative stress; however, the role of the ATM signaling pathway in vascular pathogenesis has largely remained unclear |
| 20639198 | Here, we identify ATM to regulate oxidative stress-induced endothelial cell dysfunction and premature senescence |
| 20639198 | Oxidative stress induced senescence in endothelial cells through activation/phosphorylation of ATM by way of an Akt/p53/p21-mediated pathway |
| 20639198 | These actions were abrogated in cells in which ATM was knocked down by RNA interference or inhibited by specific inhibitory compounds |
| 20639198 | Furthermore, the in vivo significance of this regulatory pathway was confirmed using ATM knock-out mice in which induction of senescent endothelial cells in the aorta in a diabetic mouse model of endothelial dysfunction and senescence was attenuated in contrast to pathological changes seen in wild-type mice |
| 20639198 | Collectively, our results show that ATM through an ATM/Akt/p53/p21-dependent signaling pathway mediates an instructive role in oxidative stress-induced endothelial dysfunction and premature senescence |
| 20535839 | Telomeric plasmid induces human cancer cell dysfunction depending on ATM activity |
| 20214620 | Important mechanisms ensuring the stop of genomically altered cells to proliferate are the activation of ATM, p53 and the DNA damage response (DDR) |
| 20157570 | Mechanistically, we uncovered that premature senescence of lung fibroblasts induced by oxidative stress occurred through activation of an ataxia telangiectasia-mutated (ATM)/p53-depedent pathway following sequestration of the catalytic subunit of protein phosphatase 2A (PP2A-C), an inhibitor of ATM, by caveolin-1 into caveolar membranes |
| 20157118 | In response to clastogens, the ataxia telangiectasia mutated (ATM) protein is rapidly activated, which in turn initiates a cascade of DNA damage response |
| 20157118 | We found that the ATM pathway is activated by the selenium compounds, and the kinase activity is required for the selenium-induced senescence response |
| 20157118 | Pretreatment of the MRC-5 non-cancerous cells with the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl suppresses the selenium-induced ATM activation and senescence |
| 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 |
| 20042274 | ATM ST1968 |
| 20042274 | In contrast, the squamous carcinoma KB cells exhibited activation of ATR-Chk1 pathway, a persistent G(2)/M-phase arrest, cellular senescence, mitotic catastrophe and delayed apoptosis, suggesting a defective ATM pathway |
| 20042274 | Inhibition of ATM in A2780 cells, resulting in reduced phosphorylation of Chk2, enhanced ST1968-induced apoptosis, but had no effect in KB cells |
| 20042274 | The susceptibility to camptothecin-induced apoptosis of A2780 cells was likely p53-dependent but not related to the activation of the ATM pathway |
| 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 |
| 19597488 | ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence |
| 19421407 | Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression |
| 19421407 | We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression |
| 19324671 | A novel ataxia-telangiectasia mutated autoregulatory feedback mechanism in murine embryonic stem cells |
| 19324671 | Ataxia-telangiectasia mutated (ATM) is known to play a central role in effecting the DNA damage response that protects somatic cells from potentially harmful mutations, and in this role it is a key anti-cancer agent |
| 19324671 | A better understanding of the mechanisms of ATM regulation is therefore important both in prevention and treatment of disease |
| 19324671 | While progress has been made in elucidating the key signal transduction pathways that mediate damage response in somatic cells, relatively little is known about whether these function similarly in pluripotent embryonic stem (ES) cells where ATM is also implicated in our understanding of adult stem cell ageing and in improvements in regenerative medicine |
| 19324671 | There is some evidence that different mechanisms may operate in ES cells and that our understanding of the mechanisms of ATM regulation is therefore incomplete |
| 19324671 | We subjected the cells to the DNA-damaging agent doxorubicin, a drug that induces double-strand breaks, and measured ATM expression levels |
| 19324671 | We found that basal ATM gene expression was unaffected by doxorubicin treatment |
| 19324671 | However, following ATM kinase inhibition using a specific ATM inhibitor, we observed a significant increase in ATM and ataxia-telangiectasia and Rad3 related transcription |
| 19324671 | The predictions of the model are consistent both with our in vitro experiments and with in vivo studies of ATM expression in somatic cells in mice, and we hypothesize that this feedback operates in both somatic and ES cells in vivo |
| 19324671 | The results point to a possible new target for ATM inhibition that overcomes the restorative potential of the proposed feedback |
| 19306530 | RECENT FINDINGS: In mice, there is recent progress in understanding the differences in distribution of two distinct phenotypes of ATM classes with respect to dead adipocytes |
| 19306530 | The predominant ATM phenotype in obese humans may be M2, which would contrast with the M1 ATMs of obese mouse models |
| 19098271 | Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) pharmacologic inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle |
| 19071156 | Knockdown of ATM kinase or IFI16 rescued IFN-gamma-induced cellular senescence |
| 19001874 | Senescent cells accumulate senescence-associated DDR foci (SDFs) containing the activated form of ATM, its phosphorylated substrates and gammaH2AX |
| 19001874 | Importantly, inactivation of ATM in senescent MEFs allows escape from senescence and progression through the S-phase |
| 19001874 | Therefore, MEFs undergoing cellular senescence arrest their proliferation due to the activation of a DNA damage checkpoint mediated by ATM kinase |
| 18723444 | We show that human atherosclerotic plaque VSMCs exhibit increased levels of double-stranded DNA breaks and basal activation of DNA repair pathways involving ataxia telangiectasia-mutated (ATM) and the histone H2AX in vivo and in vitro |
| 18723444 | Statin treatment reduced VSMC senescence and telomere attrition in culture, accelerated DNA repair and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR (ATM and Rad3-related) activity in atherosclerosis |
| 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 | The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values |
| 18608517 | Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study |
| 18608517 | Treatment with inflammatory cytokines generated reactive oxygen species (ROS) in cultured BECs followed by activation of the ATM/p53/p21(WAF1/Cip1) pathway and the induction of cellular senescence |
| 18608517 | Pre-treatment with ATM inhibitor (2-aminopurine) and antioxidant (N-acetylcysteine) significantly blocked the cellular senescence of BECs induced by oxidative stress or inflammatory cytokines |
| 18608517 | In conclusion, proinflammatory cytokines induce ROS generation and activate the ATM/p53/p21(WAF1/Cip1) pathway, followed by biliary epithelial senescence |
| 18497977 | WI-38 and A549 cells were exposed to 200 microM H2O2 in the absence or presence of HA and induction of histone H2AX phosphorylation and activation of ATM, the reporters of DNA damage, was assessed by multiparameter cytometry |
| 18440596 | Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo |
| 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 |
| 18440596 | After experimental induction of cellular senescence in the livers of juvenile mice, there was robust expression of DDR markers in hepatocytes at 1 week; however, by 7 weeks, activation of ATM/ATR kinase targets was limited, although cells with DNA damage foci were present |
| 18440596 | An analysis of hepatocytes of aged, 22-month-old mice, not experimentally exposed to genotoxins, showed limited activation of ATM/ATR targets, though high numbers of cells with DNA damage foci were found, similar to that seen many weeks after artificial senescence induction in young mice |
| 18429962 | In 3 of 6 clinical ATC samples, miR-17-3p and miR-17-5p were robustly overexpressed in cancer lesions compared to adjacent normal tissue |
| 18429962 | In conclusion, these findings suggest that the miR-17-92 cluster plays an important role in certain types of ATCs and could be a novel target for ATC treatment |
| 18347191 | Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy |
| 18347191 | Using immunofluorescence and flow cytometry-based techniques, we established the status of the ataxia telangiectasia mutated (ATM) signaling pathway in these cells |
| 18347191 | We assayed the requirement of ATM signaling and p21(CIP1) expression for survival in premature senescent tumor cells using pharmacologic inhibitors and antisense oligonucleotides |
| 18347191 | RESULTS: The ATM/ATR (ATM- and Rad3-related) signaling pathway was found to be constitutively active in drug-induced senescent tumor cells |
| 18347191 | We found that blocking ATM/ATR signaling with pharmacologic inhibitors, including the novel ATM inhibitors KU55933 and CGK733, induced senescent breast, lung, and colon carcinoma cells to undergo cell death |
| 18347191 | We show that the mechanism of action of this effect is directly via p21(CIP1), which acts downstream of ATM |
| 18347191 | This is in contrast to the effects of ATM inhibitors on normal, untransformed senescent cells |
| 18347191 | CONCLUSIONS: Blocking ATM and/or p21(CIP1) following initial treatment with a low dose of senescence-inducing chemotherapy is a potentially less toxic and highly specific treatment for carcinomas |
| 17879239 | The level of ATM activation and H2AX phosphorylation, detected immunocytochemically, has been monitored in WI-38, A549, and TK6 cells treated with H2O2 as well as growing under conditions known or suspected to affect the level of endogenous oxidants |
| 17879239 | Thirty- to 60-min exposure of cells to 100 or 200 microM H2O2 led to an increase in the level of H2AX phosphorylation and ATM activation, particularly pronounced (nearly fivefold) in S-phase cells |
| 17875940 | Inhibition of ATM kinase prevents induction of senescence, implying that senescence is a consequence of DNA damage |
| 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 |
| 17687332 | When telomeres are rendered dysfunctional through replicative attrition of the telomeric DNA or by inhibition of shelterin, cells show the hallmarks of ataxia telangiectasia mutated (ATM) kinase signalling |
| 17687332 | Here we show that damaged mammalian telomeres can activate both ATM and ATR and address the mechanism by which the shelterin complex represses these two important DNA damage signalling pathways |
| 17687332 | Unexpectedly, we found that either ATM or ATR signalling is required for efficient non-homologous end-joining of dysfunctional telomeres |
| 17664422 | The pharmacologic inhibition of signaling pathways implicated in oncogene-induced senescence including ATM/ATR and MAPK did not prevent senescence associated with MYC inactivation |
| 17562874 | In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity |
| 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) |
| 17562874 | Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity |
| 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 |
| 17227291 | Constitutive histone H2AX phosphorylation and ATM activation are strongly amplified during mitogenic stimulation of lymphocytes |
| 17206596 | Failure to express an intact ATM/CHK2 DNA damage signalling pathway in either cell type leads to a delay in the PML-ND response to IR |
| 17116315 | We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age |
| 17097049 | It has been shown that ataxia telangiectasia-mutated (ATM) is required for meiotic division of the seminiferous tubules |
| 17097049 | Here, we show that, in addition to its role in meiosis, ATM has a pivotal role in premeiotic germ cell maintenance |
| 17097049 | ATM is activated in premeiotic spermatogonial cells and the Atm-null testis shows progressive degeneration |
| 16840774 | The decrease in proliferation was accompanied by increased ATM, p53, and p21 activity |
| 16767085 | Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia-mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733 |
| 16767085 | Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC), we identified ATM as the molecular target of CGK733 from a genome-wide screen |
| 16767085 | CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity |
| 16767085 | Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733 |
| 16767085 | These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation |
| 16456035 | In addition, the same cells contain activated ataxia-telangiectasia mutated kinase and heterochromatinized nuclei, confirming their senescent status |
| 16319536 | This suggestion is in agreement with a growing body of evidence demonstrating that HSCs from Bmi-1(-/-) and ATM(-/-) mice can lose their ability to self-renew by undergoing premature senescence |
| 15769667 | Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment |
| 15734488 | MATERIALS AND METHODS: A unique pressure incubator was used to culture NNF at atmospheric pressure (ATM), ATM + 30 mmHg, ATM + 60 mmHg, and ATM +120 mmHg |
| 15734488 | RESULTS: NNF cultured at ATM + 60 mmHg and ATM + 120 mmHg showed increased SA-beta-Gal activity (P <0 |
| 15734488 | These effects were not seen at ATM + 30 mmHg |
| 15610769 | Second, the signalling pathway connecting telomere uncapping and replicative senescence appears to be the same as the one that is activated by DNA damage: uncapped telomeres activate signalling cascades involving the protein kinases ATM, ATR and, possibly, DNA-PK |
| 15172978 | Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts |
| 15172978 | Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells |
| 15172978 | The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction |
| 15172978 | Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence |
| 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 |
| 15149599 | Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling |
| 15149599 | ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest |
| 15000677 | Natural regulation of TERF1 involves tankyrase, ATM protein kinase, and fluctuations of the protein level across a cell cycle |
| 12072449 | Regulation of genome stability by TEL1 and MEC1, yeast homologs of the mammalian ATM and ATR genes |
| 12072449 | In the yeast Saccharomyces cerevisiae, two members of this family, TEL1 and MEC1, have functionally redundant roles in both DNA damage repair and telomere length regulation |
| 12072449 | Similar chromosome rearrangements have been detected in mammalian cells with mutations in ATM (related to TEL1) and ATR (related to MEC1) and in mammalian cells that approach cell crisis |
| 11333225 | Mec1p is a cell cycle checkpoint protein related to the ATM protein kinase family |
| 11297767 | Malignancy develops years later, after additional chromosomal changes resulting from the genomic instability consequent to ATM disruption and to the activation of the TCL1 oncogene |
| 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 |
| 9405657 | Modification of these two crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for atm and p21 |
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