Cyclin-dependent kinase 4
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| Location (UCSC) | Chr 12: 57.75 – 57.76 Mb | n/a | |||||||
| PubMed search | [2] | [3] | |||||||
| View/Edit Human | View/Edit Mouse |
Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.
Function
The protein encoded by this gene is a member of the
SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.[5]
Clinical significance
Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers. One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly. Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials.[6][7]
Multiple polyadenylation sites of this gene have been reported.[4]
It is regulated by Cyclin D.
Inhibitors
US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative advanced breast cancer.[8]
See also CDK inhibitor for inhibitors of various CDKs.
Interactions
Cyclin-dependent kinase 4 has been shown to
interact
with:
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000135446 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: CDK4 cyclin-dependent kinase 4".
- ^ "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein".
- S2CID 12933349.
- PMID 30959874.
- ^ "Approved Drugs > Ribociclib (Kisqali)". Food and Drug Administration. Retrieved 12 September 2017.
- ^ PMID 17353931.
- PMID 8703009.
- S2CID 25236893.
- PMID 8666233.
- ^ S2CID 25204152.
- ^ PMID 10908655.
- ^ S2CID 4427026.
- S2CID 7410135.
- PMID 8001816.
- PMID 11684017.
- ^ PMID 10580009.
- ^ S2CID 4270052.
- PMID 9837900.
- ^ PMID 9228064.
- PMID 14641107.
- S2CID 45094232.
- PMID 10601020.
- PMID 10022835.
- S2CID 23024663.
- ^ PMID 15065884.
- PMID 8101826.
Further reading
- Hanks SK (1987). "Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family". Proc. Natl. Acad. Sci. U.S.A. 84 (2): 388–92. PMID 2948189.
- Hall M; Bates S; Peters G (1995). "Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins". Oncogene. 11 (8): 1581–8. PMID 7478582.
- Tassan JP, Jaquenoud M, Léopold P, et al. (1995). "Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C". Proc. Natl. Acad. Sci. U.S.A. 92 (19): 8871–5. PMID 7568034.
- Mitchell EL, White GR, Santibanez-Koref MF, et al. (1995). "Mapping of gene loci in the Q13-Q15 region of chromosome 12". Chromosome Res. 3 (4): 261–2. S2CID 6029915.
- Wölfel T, Hauer M, Schneider J, et al. (1995). "A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma". Science. 269 (5228): 1281–4. S2CID 37848897.
- Hirai H, Roussel MF, Kato JY, et al. (1995). "Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6". Mol. Cell. Biol. 15 (5): 2672–81. PMID 7739547.
- Chan FK, Zhang J, Cheng L, et al. (1995). "Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4". Mol. Cell. Biol. 15 (5): 2682–8. PMID 7739548.
- Guan KL, Jenkins CW, Li Y, et al. (1995). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes Dev. 8 (24): 2939–52. PMID 8001816.
- Kato JY; Matsuoka M; Strom DK; Sherr CJ (1994). "Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase". Mol. Cell. Biol. 14 (4): 2713–21. PMID 8139570.
- Khatib ZA, Matsushime H, Valentine M, et al. (1993). "Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas". Cancer Res. 53 (22): 5535–41. PMID 8221695.
- Serrano M; Hannon GJ; Beach D (1994). "A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4". Nature. 366 (6456): 704–7. S2CID 4368128.
- Demetrick DJ; Zhang H; Beach DH (1994). "Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes". Cytogenet. Cell Genet. 66 (1): 72–4. PMID 8275715.
- Kato J, Matsushime H, Hiebert SW, et al. (1993). "Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4". Genes Dev. 7 (3): 331–42. PMID 8449399.
- Zuo L, Weger J, Yang Q, et al. (1996). "Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma". Nat. Genet. 12 (1): 97–9. S2CID 29727436.
- Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. PMID 8619474.
- Knudsen ES; Wang JY (1996). "Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites". J. Biol. Chem. 271 (14): 8313–20. PMID 8626527.
- Poon RY; Jiang W; Toyoshima H; Hunter T (1996). "Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage". J. Biol. Chem. 271 (22): 13283–91. PMID 8662825.
- Stepanova L; Leng X; Parker SB; Harper JW (1996). "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes Dev. 10 (12): 1491–502. PMID 8666233.
- Dai K; Kobayashi R; Beach D (1996). "Physical interaction of mammalian CDC37 with CDK4". J. Biol. Chem. 271 (36): 22030–4. PMID 8703009.
- Fåhraeus R, Paramio JM, Ball KL, et al. (1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A" (PDF). Curr. Biol. 6 (1): 84–91. S2CID 23024663.
External links
- Cyclin-Dependent+Kinase+4 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- CDK4 human gene location in the UCSC Genome Browser.
- CDK4 human gene details in the UCSC Genome Browser.
