HCSGD entry for CDK4
1. General information
| Official gene symbol | CDK4 |
|---|---|
| Entrez ID | 1019 |
| Gene full name | cyclin-dependent kinase 4 |
| Other gene symbols | CMM3 PSK-J3 |
| Links to Entrez Gene | Links to Entrez Gene |
2. Neighbors in the network
3. Gene ontology annotation
GO ID | GO term | Evidence | Category |
|---|---|---|---|
| GO:0000082 | G1/S transition of mitotic cell cycle | IMP | biological_process |
| GO:0000278 | Mitotic cell cycle | TAS | biological_process |
| GO:0000307 | Cyclin-dependent protein kinase holoenzyme complex | IDA IEA | cellular_component |
| GO:0000785 | Chromatin | IDA | cellular_component |
| GO:0004672 | Protein kinase activity | IEA | molecular_function |
| GO:0004674 | Protein serine/threonine kinase activity | IEA | molecular_function |
| GO:0004693 | Cyclin-dependent protein serine/threonine kinase activity | IDA IEA | molecular_function |
| GO:0005515 | Protein binding | IPI | molecular_function |
| GO:0005524 | ATP binding | IEA | molecular_function |
| GO:0005634 | Nucleus | IDA IEA | cellular_component |
| GO:0005654 | Nucleoplasm | TAS | cellular_component |
| GO:0005667 | Transcription factor complex | IEA | cellular_component |
| GO:0005730 | Nucleolus | IDA | cellular_component |
| GO:0005829 | Cytosol | IDA TAS | cellular_component |
| GO:0005923 | Tight junction | IEA | cellular_component |
| GO:0006468 | Protein phosphorylation | IDA | biological_process |
| GO:0007165 | Signal transduction | IEA | biological_process |
| GO:0007623 | Circadian rhythm | IEA | biological_process |
| GO:0008284 | Positive regulation of cell proliferation | IEA IMP | biological_process |
| GO:0009636 | Response to toxic substance | IEA | biological_process |
| GO:0010288 | Response to lead ion | IEA | biological_process |
| GO:0010468 | Regulation of gene expression | IMP | biological_process |
| GO:0010971 | Positive regulation of G2/M transition of mitotic cell cycle | IDA | biological_process |
| GO:0030332 | Cyclin binding | IEA IPI | molecular_function |
| GO:0031100 | Organ regeneration | IEA | biological_process |
| GO:0031965 | Nuclear membrane | IDA | cellular_component |
| GO:0032403 | Protein complex binding | IEA | molecular_function |
| GO:0033574 | Response to testosterone | IEA | biological_process |
| GO:0042493 | Response to drug | IGI | biological_process |
| GO:0043065 | Positive regulation of apoptotic process | IEA | biological_process |
| GO:0045727 | Positive regulation of translation | IEA | biological_process |
| GO:0045793 | Positive regulation of cell size | IEA | biological_process |
| GO:0048146 | Positive regulation of fibroblast proliferation | IMP | biological_process |
| GO:0048471 | Perinuclear region of cytoplasm | IEA | cellular_component |
| GO:0051301 | Cell division | IEA | biological_process |
| GO:0051726 | Regulation of cell cycle | IEA | biological_process |
| GO:0055093 | Response to hyperoxia | IEA | biological_process |
| GO:0071157 | Negative regulation of cell cycle arrest | IDA | biological_process |
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4. Expression levels in datasets
- Meta-analysis result
| p-value up | p-value down | FDR up | FDR down |
|---|---|---|---|
| 0.8660244786 | 0.0088611071 | 0.9999902473 | 0.1868855769 |
- 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 | 1.0248253253 |
| GSE13712_SHEAR | Down | -0.6240253794 |
| GSE13712_STATIC | Down | -0.2915793770 |
| GSE19018 | Down | -0.3326021712 |
| GSE19899_A1 | Down | -0.7060893699 |
| GSE19899_A2 | Down | -0.6102384182 |
| PubMed_21979375_A1 | Down | -0.7793093106 |
| PubMed_21979375_A2 | Down | -0.8062438531 |
| GSE35957 | Down | -0.6566978944 |
| GSE36640 | Down | -1.3438457796 |
| GSE54402 | Up | 0.1534077088 |
| GSE9593 | Up | 0.0261456863 |
| GSE43922 | Down | -0.3884860385 |
| GSE24585 | Down | -0.3396386339 |
| GSE37065 | Down | -0.2488677934 |
| GSE28863_A1 | Up | 0.0747870958 |
| GSE28863_A2 | Up | 0.5605067488 |
| GSE28863_A3 | Down | -0.4799805038 |
| GSE28863_A4 | Up | 0.1905032019 |
| GSE48662 | Down | -0.4639226742 |
5. Regulation relationships with compounds/drugs/microRNAs
- Compounds
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- Drugs
Name | Drug | Accession number |
|---|---|---|
| Purvalanol | DB02733 | EXPT02705 |
| Flavopiridol | DB03496 | EXPT00998 |
| Palbociclib | DB09073 | - |
- MicroRNAs
- mirTarBase
MiRNA_name | mirBase ID | miRTarBase ID | Experiment | Support type | References (Pubmed ID) |
|---|---|---|---|---|---|
| hsa-miR-24-3p | MIMAT0000080 | MIRT000117 | Luciferase reporter assay//Microarray//qRT-PCR//Western blot//Reporter assay;Western blot;qRT-PCR;Other | Functional MTI | 19748357 |
| hsa-miR-34a-5p | MIMAT0000255 | MIRT000763 | Luciferase reporter assay | Functional MTI | 19461653 |
| hsa-miR-34a-5p | MIMAT0000255 | MIRT000763 | Luciferase reporter assay//Western blot//Microarray | Functional MTI | 17914404 |
| hsa-miR-34a-5p | MIMAT0000255 | MIRT000763 | qRT-PCR | Functional MTI (Weak) | 21240262 |
| hsa-miR-34a-5p | MIMAT0000255 | MIRT000763 | Western blot | Functional MTI | 21128241 |
| hsa-miR-34b-5p | MIMAT0000685 | MIRT000764 | Luciferase reporter assay | Functional MTI | 19461653 |
| hsa-miR-34c-5p | MIMAT0000686 | MIRT000765 | Luciferase reporter assay | Functional MTI | 19461653 |
| hsa-miR-34c-5p | MIMAT0000686 | MIRT000765 | Microarray//Western blot//RTPCR | Functional MTI | 20924086 |
| hsa-miR-124-3p | MIMAT0000422 | MIRT002625 | Microarray | Functional MTI (Weak) | 15685193 |
| hsa-miR-124-3p | MIMAT0000422 | MIRT002625 | Proteomics;Microarray | Non-Functional MTI (Weak) | 18668037 |
| hsa-miR-124-3p | MIMAT0000422 | MIRT002625 | Luciferase reporter assay//Western blot | Functional MTI | 23761023 |
| hsa-miR-195-5p | MIMAT0000461 | MIRT006252 | Luciferase reporter assay | Functional MTI | 22289176 |
| hsa-miR-34b-3p | MIMAT0004676 | MIRT003450 | Microarray//Western blot//RTPCR | Functional MTI | 20924086 |
| hsa-miR-302a-3p | MIMAT0000684 | MIRT003636 | Luciferase reporter assay//qRT-PCR//Western blot | Functional MTI | 18710938 |
| hsa-miR-145-5p | MIMAT0000437 | MIRT005879 | Luciferase reporter assay//qRT-PCR//Western blot | Functional MTI | 21092188 |
| hsa-miR-449b-5p | MIMAT0003327 | MIRT016137 | Western blot | Non-Functional MTI | 19833767 |
| hsa-miR-449a | MIMAT0001541 | MIRT016631 | Western blot | Functional MTI | 19833767 |
| hsa-miR-155-5p | MIMAT0000646 | MIRT021016 | Proteomics | Functional MTI (Weak) | 18668040 |
| hsa-miR-122-5p | MIMAT0000421 | MIRT023403 | Reporter assay | Functional MTI | 21750653 |
| hsa-miR-1 | MIMAT0000416 | MIRT024107 | Proteomics;Microarray | Non-Functional MTI (Weak) | 18668037 |
| hsa-miR-766-3p | MIMAT0003888 | MIRT039027 | CLASH | Functional MTI (Weak) | 23622248 |
| hsa-miR-193b-3p | MIMAT0002819 | MIRT041351 | CLASH | Functional MTI (Weak) | 23622248 |
| hsa-miR-320a | MIMAT0000510 | MIRT044439 | CLASH | Functional MTI (Weak) | 23622248 |
| hsa-miR-15b-5p | MIMAT0000417 | MIRT046412 | CLASH | Functional MTI (Weak) | 23622248 |
| hsa-miR-25-3p | MIMAT0000081 | MIRT050205 | 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-24-3p | MIMAT0000080 | 1 | hsa-miR-24 | 19748357 |
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6. Text-mining results about the gene
Gene occurances in abstracts of cellular senescence-associated articles: 56 abstracts the gene occurs.
PubMed ID of the article | Sentenece the gene occurs |
|---|---|
| 27206849 | A CDK4/6-Dependent Epigenetic Mechanism Protects Cancer Cells from PML-induced Senescence |
| 27206849 | Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression |
| 27206849 | Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization |
| 27206849 | Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells |
| 26977878 | Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors |
| 26977878 | This is overcome using CDK4/6 inhibitors |
| 26977878 | Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity |
| 26977878 | Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity |
| 26977878 | In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer |
| 26719346 | METHODS: Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i) |
| 26529363 | Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c-Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1-mediated transcriptional repression of E2F |
| 26528855 | Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA |
| 26528855 | Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on CDK4/6 activity |
| 26528855 | Thus, CDK4/6 activity appears to represent a promising therapeutic target for cancer treatment |
| 26528855 | In the present work, we explore the efficacy of CDK4 inhibition using palbociclib (PD0332991), a highly selective inhibitor of CDK4/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs) |
| 26528855 | Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4 mRNA |
| 26528855 | Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a |
| 26528855 | The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors |
| 26528855 | In summary, our data support the efficacy of CDK4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST |
| 26528855 | Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors |
| 26292757 | We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21(Cip1) and p27(Kip1) proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors |
| 26292757 | Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues |
| 26292757 | Interestingly, complete abrogation of p21(Cip1) and p27(Kip1) in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues |
| 26292757 | Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors |
| 26215037 | Western blot was used to assess SHP-1, p21, p53, pRb, Rb, H3K9Me3, HP1gamma, CDK4, cyclin D1, cyclin E, and p16 protein expressions |
| 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 |
| 25882843 | Mito-Pim1 increases the proliferation rate by up-regulation of cell cycle modulators Cyclin D, CDK4, and phospho-Rb |
| 25698448 | Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly |
| 25695870 | In studying conditional senescence in human fibroblasts that express a temperature sensitive SV40 large T-antigen (T-Ag), we uncovered an unexpected role for CDK4 |
| 25695870 | In exploring whether the reassembled cyclin D-CDK4-p21 complexes are functional, we found that shRNA-mediated knockdown or chemical inhibition of CDK4 prevented the increase in cell size associated with the senescent phenotype by allowing the cells to arrest in G1 rather than G2/M |
| 25695870 | The data point to a role for CDK4 kinase activity in a G2 checkpoint that contributes to senescence |
| 25693733 | Fucoidan also promoted the expression of cell cycle-associated proteins (cyclin E, Cdk2, cyclin D1, and Cdk4) in senescent ECFCs, significantly reversed cellular senescence, and increased the proliferation of ECFCs via the FAK, Akt, and ERK signaling pathways |
| 25675863 | In BCR-ABL1+ ALLs, high CDK4 expression, phosphorylated pRb (p-pRb) and telomerase activity were significantly associated with a shorter disease-free survival (DFS) and event-free survival (EFS) |
| 25481981 | Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition |
| 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 |
| 25229346 | Tissue taurine depletion in taurine transporter knockout (TauTKO) mouse was found to shorten lifespan and accelerate skeletal muscle histological and functional defects, including an increase in central nuclei containing myotubes, a reduction in mitochondrial complex 1 activity and an induction in an aging biomarker, Cyclin-dependent kinase 4 inhibitor A (p16INK4a) |
| 25181340 | Hydrogen peroxide also suppressed the expression of phosphorylated Rb and CDK4, resulting in arrest in G0/G1 phase in NHEKs, but not SCCs |
| 25132913 | Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P < 0 |
| 24807532 | Furthermore, upregulation of p16(INK4a) was critical to the antitumor activity of HepG2 cells treated with fucoidan and was correlated with inhibition of Cdk4 and pRb and upregulation of p21 expression |
| 24393841 | In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex |
| 24089445 | The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma |
| 24089445 | The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease |
| 24089445 | The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1-S cell-cycle transition |
| 24089445 | In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis |
| 24089445 | In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16(INK4A)) is deleted |
| 24089445 | A central question is whether melanomas with activating events in the CDK4 pathway have become "addicted" to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression |
| 24089445 | Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit |
| 24089445 | This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma |
| 24046371 | The tumor suppressor p16(INK4A) inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins |
| 24046371 | This oncogenic p16(INK4A) activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive |
| 24045179 | Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma |
| 24045179 | Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes |
| 24045179 | EXPERIMENTAL PROCEDURES: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor |
| 24045179 | CONCLUSIONS: Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease |
| 23852369 | We confirmed that the inhibitor of CDK4/6 caused cyclin D1 positive senescence in normal RPE cells, whereas U0126 prevented cyclin D1 expression |
| 23620010 | In agreement with the cell cycle arrest, ox-LDL markedly reduced the expression of CDK4, cyclin D, and cyclin E |
| 23316069 | We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4) |
| 23316069 | Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity |
| 23316069 | NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells |
| 23284695 | Colonies of these uniform and hexagonal HCEnCs (HCEnC-21) were selectively isolated and demonstrated high proliferative potential that was dependent on endogenous upregulation of telomerase and cyclin D/CDK4 |
| 22855034 | At the end of the 48-h culture, the following analyses were performed including determination of senescence-associated beta-galactosidase (SAbeta-Gal) activity, flow cytometry analysis of cell cycle, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses of p16, Cyclin D1, cyclin-dependent kinase 4 (CDK4) and retinoblastoma (Rb) mRNA expression, and Western blotting analyses of p16, cyclin D1, CDK4 and phosphoretinoblastoma (pRb) protein expressions |
| 22855034 | Compared with the old group, VSMCs in the treated groups had a significant increase in p16 and Rb mRNA expression and a significant decrease in Cyclin D1 and CDK4 mRNA expression (P<0 |
| 22855034 | Compared with the old group, VSMCs in the treated groups had a significant increase in p16 protein expression and a significant decrease in cyclinD1, CDK4 and pRb protein expressions (P<0 |
| 22820504 | The expression of p16(INK4A) was significantly increased, whereas levels of CDK4, CDK6 and p-Rb expression were decreased in the MSCs from both untreated and treated SLE patients |
| 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 |
| 21613412 | Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways |
| 21613412 | Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence |
| 21613412 | These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors |
| 21367843 | Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed |
| 21289643 | Consistently, coexpression of JunB and Ras induced premature epidermal differentiation concomitant with upregulation of p16 and filaggrin and downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4) |
| 21263217 | In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines |
| 21047732 | Paradoxically, G(1)-S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G(1) arrest |
| 20938386 | Total RNA isolated from these samples was used to measure the gene expression of p16INK4a, RB, cyclin D1, CDK4, PTEN, p27KIP, p19ARF, p21, TERT, and RAGE by real-time polymerase chain reaction assay |
| 20938386 | The increased cyclin D1 mRNA level was statistically significant only at the ninth month following amputation; CDK4 and TERT mRNA levels were downregulated to a similar extent at both points compared with nonamputated controls |
| 19098430 | In contrast, the levels of cyclin D1, CDK4 and CDK6 were sharply decreased |
| 18843795 | We also show that overexpression of CDK4, or its homologue CDK6, but not the downstream kinase, CDK2, inhibited the ability of wild-type p16(INK4a) to promote cell cycle arrest and senescence |
| 18843795 | Our data provide the first evidence that p16(INK4a) can initiate a CDK4/6-dependent autonomous senescence programme that is disabled by inherited melanoma-associated mutations |
| 17559502 | Cellular senescence in human myoblasts is overcome by human telomerase reverse transcriptase and cyclin-dependent kinase 4: consequences in aging muscle and therapeutic strategies for muscular dystrophies |
| 17559502 | We describe here the production and characterization of a human myogenic cell line, LHCN-M2, that has overcome replicative aging due to the expression of telomerase and cyclin-dependent kinase 4 |
| 16901784 | These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers |
| 15657429 | Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7 |
| 15460900 | The p16INK4a tumor suppressor protein functions as an inhibitor of CDK4 and CDK6, the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB |
| 14604992 | 2) Expression of a p16(INK4a)-insensitive form of CDK4 obstructs hSNF5-induced cell cycle arrest |
| 13679081 | The cell cycle-associated proteins such as cyclin D1, cyclin E, CDK2, and CDK4, and kinase activities associated with CDK2 and CDK4 were increased in aged MASMC |
| 12789281 | Special reference is made to the fact that the known melanoma susceptibility genes in the human, Inhibitor A of [cyclin-dependent] kinase 4-alternative reading frame (INK4A-ARF) and cyclin-dependent kinase 4, are involved in the regulation of cellular senescence, and possible reasons why this should be so |
| 12100489 | The three genes so far associated with familial melanoma susceptibility--INK4A, CDK4 and ARF, are all implicated in the molecular pathways controlling cell senescence |
| 11756559 | Mutations in CDK4 and its key kinase inhibitor p16(INK4a) have been implicated in the genesis and progression of familial human melanoma |
| 11756559 | The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16(INK4a) |
| 11756559 | To determine the role of the Cdk4(R24C) germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by using Cre-loxP-mediated "knock-in" technology |
| 11756559 | Cdk4(R24C/R24C) mouse embryo fibroblasts (MEFs) displayed increased Cdk4 kinase activity resulting in hyperphosphorylation of all three members of the Rb family, pRb, p107, and p130 |
| 11756559 | This report formally establishes that the activation of Cdk4 is sufficient to promote cancer in many tissues |
| 11756559 | The observation that a wide variety of tumors develop in mice harboring the Cdk4(R24C) mutation offers a genetic proof that Cdk4 activation may constitute a central event in the genesis of many types of cancers in addition to melanoma |
| 11602203 | In addition, senescence is associated with increased binding of the cyclin-dependent kinase inhibitor (CDK-I) p16(INK4a) to CDK4, down-regulation of cyclin E protein levels (and consequent loss of cyclin E/CDK2 activity), underphosphorylation of the retinoblastoma protein RB and subsequent increased levels of E2F4-RB repressive complexes |
| 10911949 | In these cells, senescence is associated with increased binding of p16INK4a to CDK4 and loss of E2F-binding activity |
| 10911949 | This delayed senescence may result from reduced association of p16 with CDK4, reduced levels of underphosphorylated pRb, and steady levels of cyclin E and E2F1 |
| 10851091 | Within the INK4 family, this regulatory mode appears restricted to p19INK4d whose ubiquitination was dependent on the integrity of lysine 62, and binding to CDK4 |
| 10585280 | Here we present evidence that activation of a cAMP pathway correlates with multiple cellular changes in these cells: (1) increased expression of the transcription factor microphthalmia; (2) increased melanogenesis; (3) increased association of the cyclin-dependent kinase inhibitors (CDK-Is) p27(KIP1) and p16(INK4) with CDK2 and CDK4, respectively; (4) failure to phosphorylate the retinoblastoma protein (pRB); (5) decreased expression of E2F1, E2F2, and E2F4 proteins; (6) loss of E2F DNA-binding activity; and (7) phenotypic changes characteristic of senescent cells |
| 10585273 | Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: roles of p16, p21, and cyclin D1 |
| 10585273 | In the present study, we have found a severe impairment in the activation of Cdk2 and Cdk4 in response to mitogens in senescent human fibroblasts and determined the molecular basis for this |
| 10585273 | Although Cdk4 protein was constitutively expressed in senescent cells at the same level as in early-passage young cells, it was found to be complexed with a distinct set of Cdk inhibitors |
| 10585273 | Thus, one of the underlying molecular events involved in replicative senescence is the impaired activation of Cdk4 and Cdk2 due to increased binding of p16 to Cdk4 and increased association of Cdk2 with cyclin D1 and p21 |
| 9732051 | Likewise, cyclin D is complexed with its catalytic partners CDK4 and CDK6 in senescent HDF, but it is not known whether these complexes are active |
| 9732051 | In contrast, p16Ink4a, which binds monomeric CDK4 and CDK6 thereby preventing their binding to cyclin D, is increased dramatically at the time of senescence and remains high for at least 2 mo |
| 9584157 | Cyclin D2 was also found to be associated with the cyclin-dependent kinases CDK2 and CDK4 but not CDK6 during growth arrest |
| 8943005 | To determine a possible mechanism by which senescent human fibroblasts maintain a hypophosphorylated Rb, we examined the expression levels and interaction of the Rb kinases, CDK4 and CDK6, and the cyclin-dependent kinase inhibitors p21 and p16 in senescent HDFs |
| 8943005 | In senescent HDFs, p16 was shown to be complexed to both CDK4 and CDK6 |
| 8943005 | Immunodepletion analysis of p21 and p16 from the senescent cell extracts revealed that p16 is the major CDK inhibitor for both CDK4 and CDK6 kinases |
| 8943005 | Immunoprecipitation of CDK4 and CDK6 and their associated proteins from radiolabeled extracts from senescent HDFs showed no other CDK inhibitors |
| 7575495 | Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4 |
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