Cyclin-dependent kinase 4 explained

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 p16^INK4a. This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). 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, as well as phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. It is a component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.^[1]

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.^{[2] [3]}

Multiple polyadenylation sites of this gene have been reported.^[4]

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:

• CDC37,^{[6] [7] [8] [9]}
• CDKN1B,
• CDKN2B,^[10]
• CDKN2C,^{[6] [11]}
• CEBPA,^[12]
• CCND1,^{[13] [14] [15]}
• CCND3,^{[16] [17] [18] [19]}
• DBNL,^[6]
• MyoD,^{[20] [21]}
• P16,^{[6] [15] [22]}
• PCNA,^{[23] [24]} and
• SERTAD1.^{[25] [26]}

Further reading

• Hanks SK . Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family . Proceedings of the National Academy of Sciences of the United States of America . 84 . 2 . 388–392 . January 1987 . 2948189 . 304212 . 10.1073/pnas.84.2.388 . free . 1987PNAS...84..388H .
• Hall M, Bates S, Peters G . 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 . 1581–1588 . October 1995 . 7478582 .
• Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA . Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C . Proceedings of the National Academy of Sciences of the United States of America . 92 . 19 . 8871–8875 . September 1995 . 7568034 . 41069 . 10.1073/pnas.92.19.8871 . free . 1995PNAS...92.8871T .
• Mitchell EL, White GR, Santibanez-Koref MF, Varley JM, Heighway J . Mapping of gene loci in the Q13-Q15 region of chromosome 12 . Chromosome Research . 3 . 4 . 261–262 . June 1995 . 7606365 . 10.1007/BF00713052 . 6029915 .
• Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Büschenfelde KH, Beach D . A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma . Science . 269 . 5228 . 1281–1284 . September 1995 . 7652577 . 10.1126/science.7652577 . 37848897 . 1995Sci...269.1281W .
• Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ . Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 . Molecular and Cellular Biology . 15 . 5 . 2672–2681 . May 1995 . 7739547 . 230497 . 10.1128/MCB.15.5.2672 .
• Chan FK, Zhang J, Cheng L, Shapiro DN, Winoto A . Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4 . Molecular and Cellular Biology . 15 . 5 . 2682–2688 . May 1995 . 7739548 . 230498 . 10.1128/MCB.15.5.2682 .
• Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y . Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function . Genes & Development . 8 . 24 . 2939–2952 . December 1994 . 8001816 . 10.1101/gad.8.24.2939 . free .
• Kato JY, Matsuoka M, Strom DK, Sherr CJ . Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase . Molecular and Cellular Biology . 14 . 4 . 2713–2721 . April 1994 . 8139570 . 358637 . 10.1128/MCB.14.4.2713 .
• Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT . Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas . Cancer Research . 53 . 22 . 5535–5541 . November 1993 . 8221695 .
• Serrano M, Hannon GJ, Beach D . A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 . Nature . 366 . 6456 . 704–707 . December 1993 . 8259215 . 10.1038/366704a0 . 4368128 . 1993Natur.366..704S .
• Demetrick DJ, Zhang H, Beach DH . Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes . Cytogenetics and Cell Genetics . 66 . 1 . 72–74 . 1994 . 8275715 . 10.1159/000133669 .
• Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ . Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4 . Genes & Development . 7 . 3 . 331–342 . March 1993 . 8449399 . 10.1101/gad.7.3.331 . free .
• Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC . Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma . Nature Genetics . 12 . 1 . 97–99 . January 1996 . 8528263 . 10.1038/ng0196-97 . 29727436 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–113 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Knudsen ES, Wang JY . Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites . The Journal of Biological Chemistry . 271 . 14 . 8313–8320 . April 1996 . 8626527 . 10.1074/jbc.271.14.8313 . free .
• Poon RY, Jiang W, Toyoshima H, Hunter T . Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage . The Journal of Biological Chemistry . 271 . 22 . 13283–13291 . May 1996 . 8662825 . 10.1074/jbc.271.22.13283 . free .
• Stepanova L, Leng X, Parker SB, Harper JW . Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 . Genes & Development . 10 . 12 . 1491–1502 . June 1996 . 8666233 . 10.1101/gad.10.12.1491 . free .
• Dai K, Kobayashi R, Beach D . Physical interaction of mammalian CDC37 with CDK4 . The Journal of Biological Chemistry . 271 . 36 . 22030–22034 . September 1996 . 8703009 . 10.1074/jbc.271.36.22030 . free .
• Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP . Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A . Current Biology . 6 . 1 . 84–91 . January 1996 . 8805225 . 10.1016/S0960-9822(02)00425-6 . 23024663 . 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 . free .

Notes and References

1. Web site: CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein.
2. Sheppard KE, McArthur GA . The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma . Clinical Cancer Research . 19 . 19 . 5320–5328 . October 2013 . 24089445 . 10.1158/1078-0432.CCR-13-0259 . 12933349 .
3. Sobhani N, D'Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, Bernocchi O, Generali D, Otto T . Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer . Cells . 8 . 4 . 321 . April 2019 . 30959874 . 6523967 . 10.3390/cells8040321 . free .
4. Web site: Entrez Gene: CDK4 cyclin-dependent kinase 4.
5. Web site: Approved Drugs > Ribociclib (Kisqali). . 12 September 2017.
6. 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 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .
7. Dai K, Kobayashi R, Beach D . Physical interaction of mammalian CDC37 with CDK4 . The Journal of Biological Chemistry . 271 . 36 . 22030–22034 . September 1996 . 8703009 . 10.1074/jbc.271.36.22030 . free .
8. Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J . Interaction between Cdc37 and Cdk4 in human cells . Oncogene . 14 . 16 . 1999–2004 . April 1997 . 9150368 . 10.1038/sj.onc.1201036 . 25236893 .
9. Stepanova L, Leng X, Parker SB, Harper JW . Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 . Genes & Development . 10 . 12 . 1491–1502 . June 1996 . 8666233 . 10.1101/gad.10.12.1491 . free .
10. Ghavidel A, Cagney G, Emili A . A skeleton of the human protein interactome . Cell . 122 . 6 . 830–832 . September 2005 . 16179252 . 10.1016/j.cell.2005.09.006 . 7410135 . free .
11. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y . Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function . Genes & Development . 8 . 24 . 2939–2952 . December 1994 . 8001816 . 10.1101/gad.8.24.2939 . free .
12. Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA . C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 . Molecular Cell . 8 . 4 . 817–828 . October 2001 . 11684017 . 10.1016/S1097-2765(01)00366-5 . free .
13. Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM . Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells . Proceedings of the National Academy of Sciences of the United States of America . 97 . 16 . 9042–9046 . August 2000 . 10908655 . 16818 . 10.1073/pnas.160016897 . free . 2000PNAS...97.9042C .
14. Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N . Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 . The Journal of Biological Chemistry . 273 . 50 . 33279–33286 . December 1998 . 9837900 . 10.1074/jbc.273.50.33279 . free .
15. Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR . Identification of CDK4 sequences involved in cyclin D1 and p16 binding . The Journal of Biological Chemistry . 272 . 30 . 18869–18874 . July 1997 . 9228064 . 10.1074/jbc.272.30.18869 . free .
16. Lin J, Jinno S, Okayama H . Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence . Oncogene . 20 . 16 . 2000–2009 . April 2001 . 11360184 . 10.1038/sj.onc.1204375 . 25204152 .
17. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
18. Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I . A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 . The Biochemical Journal . 378 . Pt 2 . 673–679 . March 2004 . 14641107 . 1223988 . 10.1042/BJ20031765 .
19. Zhang Q, Wang X, Wolgemuth DJ . Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis . Endocrinology . 140 . 6 . 2790–2800 . June 1999 . 10342870 . 10.1210/endo.140.6.6756 . 45094232 .
20. Zhang JM, Zhao X, Wei Q, Paterson BM . Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation . The EMBO Journal . 18 . 24 . 6983–6993 . December 1999 . 10601020 . 1171761 . 10.1093/emboj/18.24.6983 .
21. Zhang JM, Wei Q, Zhao X, Paterson BM . Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 . The EMBO Journal . 18 . 4 . 926–933 . February 1999 . 10022835 . 1171185 . 10.1093/emboj/18.4.926 .
22. Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP . Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A . Current Biology . 6 . 1 . 84–91 . January 1996 . 8805225 . 10.1016/S0960-9822(02)00425-6 . 23024663 . 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 . free .
23. Nasmyth K, Hunt T . Cell cycle. Dams and sluices . Nature . 366 . 6456 . 634–635 . December 1993 . 8259207 . 10.1038/366634a0 . 4270052 . free .
24. Xiong Y, Zhang H, Beach D . Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation . Genes & Development . 7 . 8 . 1572–1583 . August 1993 . 8101826 . 10.1101/gad.7.8.1572 . free .
25. Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E . Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) . Genes & Development . 13 . 22 . 3027–3033 . November 1999 . 10580009 . 317153 . 10.1101/gad.13.22.3027 .
26. Li J, Melvin WS, Tsai MD, Muscarella P . The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner . Biochemistry . 43 . 14 . 4394–4399 . April 2004 . 15065884 . 10.1021/bi035601s . 10.1.1.386.140 .