Biology:Cyclin-dependent kinase 4

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Short description: Human protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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).[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 G1 phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenic 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

Role of CDK4, cyklin D, Rb and E2F in cell cycle regulation.

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.[3][4]

Multiple polyadenylation sites of this gene have been reported.[1]

It is regulated by Cyclin D.

Inhibitors

Ribociclib are US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative 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. ↑ 1.0 1.1 "Entrez Gene: CDK4 cyclin-dependent kinase 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1019. 
  2. ↑ "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein". https://www.uniprot.org/uniprot/P11802. 
  3. ↑ Sheppard, K. E.; McArthur, G. A. (2013-10-01). "The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma" (in en). Clinical Cancer Research 19 (19): 5320–5328. doi:10.1158/1078-0432.CCR-13-0259. ISSN 1078-0432. PMID 24089445. 
  4. ↑ Sobhani; D’Angelo; Pittacolo; Roviello; Miccoli; Corona; Bernocchi; Generali et al. (2019-04-06). "Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer" (in en). Cells 8 (4): 321. doi:10.3390/cells8040321. ISSN 2073-4409. PMID 30959874. 
  5. ↑ "Approved Drugs > Ribociclib (Kisqali)". https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546438.htm. 
  6. ↑ 6.0 6.1 6.2 6.3 "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. 2007. doi:10.1038/msb4100134. PMID 17353931. 
  7. ↑ "Physical interaction of mammalian CDC37 with CDK4". J. Biol. Chem. 271 (36): 22030–4. 1996. doi:10.1074/jbc.271.36.22030. PMID 8703009. 
  8. ↑ "Interaction between Cdc37 and Cdk4 in human cells". Oncogene 14 (16): 1999–2004. 1997. doi:10.1038/sj.onc.1201036. PMID 9150368. 
  9. ↑ "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes Dev. 10 (12): 1491–502. 1996. doi:10.1101/gad.10.12.1491. PMID 8666233. 
  10. ↑ 10.0 10.1 10.2 "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene 20 (16): 2000–9. 2001. doi:10.1038/sj.onc.1204375. PMID 11360184. 
  11. ↑ 11.0 11.1 "Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9042–6. 2000. doi:10.1073/pnas.160016897. PMID 10908655. Bibcode: 2000PNAS...97.9042C. 
  12. ↑ 12.0 12.1 "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  13. ↑ "A skeleton of the human protein interactome". Cell 122 (6): 830–2. 2005. doi:10.1016/j.cell.2005.09.006. PMID 16179252. 
  14. ↑ "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. 1994. doi:10.1101/gad.8.24.2939. PMID 8001816. 
  15. ↑ "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Mol. Cell 8 (4): 817–28. 2001. doi:10.1016/S1097-2765(01)00366-5. PMID 11684017. 
  16. ↑ 16.0 16.1 16.2 "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes Dev. 13 (22): 3027–33. 1999. doi:10.1101/gad.13.22.3027. PMID 10580009. 
  17. ↑ 17.0 17.1 17.2 "Cell cycle. Dams and sluices". Nature 366 (6456): 634–5. 1993. doi:10.1038/366634a0. PMID 8259207. 
  18. ↑ "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. 1998. doi:10.1074/jbc.273.50.33279. PMID 9837900. 
  19. ↑ 19.0 19.1 "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". J. Biol. Chem. 272 (30): 18869–74. 1997. doi:10.1074/jbc.272.30.18869. PMID 9228064. 
  20. ↑ "A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95". Biochem. J. 378 (Pt 2): 673–9. 2004. doi:10.1042/BJ20031765. PMID 14641107. 
  21. ↑ "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology 140 (6): 2790–800. 1999. doi:10.1210/endo.140.6.6756. PMID 10342870. 
  22. ↑ "Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation". EMBO J. 18 (24): 6983–93. 1999. doi:10.1093/emboj/18.24.6983. PMID 10601020. 
  23. ↑ "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". EMBO J. 18 (4): 926–33. 1999. doi:10.1093/emboj/18.4.926. PMID 10022835. 
  24. ↑ "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Curr. Biol. 6 (1): 84–91. 1996. doi:10.1016/S0960-9822(02)00425-6. PMID 8805225. https://www.pure.ed.ac.uk/ws/files/12111645/Inhibition_of_pRb_phosphorylation_and_cell_cycle_progression.pdf. 
  25. ↑ 25.0 25.1 "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry 43 (14): 4394–9. 2004. doi:10.1021/bi035601s. PMID 15065884. 
  26. ↑ "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes Dev. 7 (8): 1572–83. 1993. doi:10.1101/gad.7.8.1572. PMID 8101826. 

Further reading

External links



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