Cyclin-dependent kinase 4

CDK4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK4, CMM3, PSK-J3, cyclin-dependent kinase 4, cyclin dependent kinase 4
External IDsOMIM: 123829 MGI: 88357 HomoloGene: 55429 GeneCards: CDK4
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1019

12567

Ensembl

ENSG00000135446

ENSMUSG00000006728

UniProt

P11802

P30285

RefSeq (mRNA)

NM_052984
NM_000075

NM_009870

RefSeq (protein)

NP_000066

NP_034000

Location (UCSC)Chr 12: 57.75 – 57.76 MbChr 10: 127.06 – 127.07 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/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 Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16INK4a. This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb).[3] Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates 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.[4]

Clinical significance

Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported.[3]

It is regulated by Cyclin D.

Inhibitors

Palbociclib is US FDA approved (Feb 2015) for estrogen receptor-positive advanced breast cancer.[5]

See also CDK inhibitor for inhibitors of various CDKs.

Interactions

Cyclin-dependent kinase 4 has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. (CDK4 in the (pink) nucleus)

References

  1. "Human PubMed Reference:".
  2. "Mouse PubMed Reference:".
  3. 1 2 "Entrez Gene: CDK4 cyclin-dependent kinase 4".
  4. http://www.uniprot.org/uniprot/P11802. Missing or empty |title= (help)
  5. "FDA Approves Palbociclib for Metastatic Breast Cancer". OncLive. 3 Feb 2015.
  6. 1 2 3 4 Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. PMC 1847948Freely accessible. PMID 17353931. doi:10.1038/msb4100134.
  7. Dai K, Kobayashi R, Beach D (1996). "Physical interaction of mammalian CDC37 with CDK4". J. Biol. Chem. 271 (36): 22030–4. PMID 8703009. doi:10.1074/jbc.271.36.22030.
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  15. Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA (2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Mol. Cell. 8 (4): 817–28. PMID 11684017. doi:10.1016/S1097-2765(01)00366-5.
  16. 1 2 3 Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E (1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes Dev. 13 (22): 3027–33. PMC 317153Freely accessible. PMID 10580009. doi:10.1101/gad.13.22.3027.
  17. 1 2 3 Nasmyth K, Hunt T (1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–5. PMID 8259207. doi:10.1038/366634a0.
  18. Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N (1998). "Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1". J. Biol. Chem. 273 (50): 33279–86. PMID 9837900. doi:10.1074/jbc.273.50.33279.
  19. 1 2 Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR (1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". J. Biol. Chem. 272 (30): 18869–74. PMID 9228064. doi:10.1074/jbc.272.30.18869.
  20. Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I (2004). "A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95". Biochem. J. 378 (Pt 2): 673–9. PMC 1223988Freely accessible. PMID 14641107. doi:10.1042/BJ20031765.
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  22. Zhang JM, Zhao X, Wei Q, Paterson BM (1999). "Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation". EMBO J. 18 (24): 6983–93. PMC 1171761Freely accessible. PMID 10601020. doi:10.1093/emboj/18.24.6983.
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Further reading

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