Cyclin-dependent kinase 4

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CDK4
Protein CDK4 PDB 1LD2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDK4, CMM3, PSK-J3, cyclin-dependent kinase 4
External IDs OMIM: 123829 MGI: 88357 HomoloGene: 55429 GeneCards: 1019
RNA expression pattern
PBB GE CDK4 202246 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_052984
NM_000075

NM_009870

RefSeq (protein)

NP_000066.1

NP_034000.1

Location (UCSC) Chr 12: 57.75 – 57.76 Mb Chr 10: 127.06 – 127.07 Mb
PubMed search [1] [2]
Wikidata
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[edit]

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).[1] 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.[2]

Clinical significance[edit]

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.[1]

It is regulated by Cyclin D.

Inhibitors[edit]

Palbociclib is US FDA approved (Feb 2015) for estrogen receptor-positive advanced breast cancer.[3]

See also CDK inhibitor for inhibitors of various CDKs.

Interactions[edit]

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

Overview of signal transduction pathways involved in apoptosis.

References[edit]

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  2. ^ http://www.uniprot.org/uniprot/P11802.  Missing or empty |title= (help)
  3. ^ "FDA Approves Palbociclib for Metastatic Breast Cancer". OncLive. 3 Feb 2015. 
  4. ^ a b c d 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. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. 
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  8. ^ a b c Lin J, Jinno S, Okayama H (2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene 20 (16): 2000–9. doi:10.1038/sj.onc.1204375. PMID 11360184. 
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  11. ^ Ghavidel A, Cagney G, Emili A (2005). "A skeleton of the human protein interactome". Cell 122 (6): 830–2. doi:10.1016/j.cell.2005.09.006. 
  12. ^ Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (1994). "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. doi:10.1101/gad.8.24.2939. PMID 8001816. 
  13. ^ 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. doi:10.1016/S1097-2765(01)00366-5. PMID 11684017. 
  14. ^ a b c 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. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009. 
  15. ^ a b c Nasmyth K, Hunt T (1993). "Cell cycle. Dams and sluices". Nature 366 (6456): 634–5. doi:10.1038/366634a0. 
  16. ^ 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. doi:10.1074/jbc.273.50.33279. PMID 9837900. 
  17. ^ a b 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. doi:10.1074/jbc.272.30.18869. PMID 9228064. 
  18. ^ 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. doi:10.1042/BJ20031765. PMC 1223988. PMID 14641107. 
  19. ^ Zhang Q, Wang X, Wolgemuth DJ (1999). "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology 140 (6): 2790–800. doi:10.1210/endo.140.6.6756. PMID 10342870. 
  20. ^ 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. doi:10.1093/emboj/18.24.6983. PMC 1171761. PMID 10601020. 
  21. ^ Zhang JM, Wei Q, Zhao X, Paterson BM (1999). "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". EMBO J. 18 (4): 926–33. doi:10.1093/emboj/18.4.926. PMC 1171185. PMID 10022835. 
  22. ^ Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Curr. Biol. 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. PMID 8805225. 
  23. ^ a b Li J, Melvin WS, Tsai MD, Muscarella P (2004). "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry 43 (14): 4394–9. doi:10.1021/bi035601s. PMID 15065884. 
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Further reading[edit]

External links[edit]