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
Orthologs
SpeciesHumanMouse
Entrez

1019

12567

Ensembl

ENSG00000135446

n/a

UniProt

P11802

P30285

RefSeq (mRNA)

NM_052984
NM_000075

NM_009870
NM_001355005

RefSeq (protein)

NP_000066

NP_034000
NP_001341934

Location (UCSC)Chr 12: 57.75 – 57.76 Mbn/a
PubMed search[2][3]
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).[4] 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.[5]

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.[6][7]

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.[8]

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

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  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ a b "Entrez Gene: CDK4 cyclin-dependent kinase 4".
  5. ^ "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein".
  6. ^ Sheppard, K. E.; McArthur, G. A. (2013-10-01). "The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma". Clinical Cancer Research. 19 (19): 5320–5328. doi:10.1158/1078-0432.CCR-13-0259. ISSN 1078-0432. PMID 24089445. S2CID 12933349.
  7. ^ Sobhani; D’Angelo; Pittacolo; Roviello; Miccoli; Corona; Bernocchi; Generali; Otto (2019-04-06). "Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer". Cells. 8 (4): 321. doi:10.3390/cells8040321. ISSN 2073-4409. PMC 6523967. PMID 30959874.
  8. ^ "Approved Drugs > Ribociclib (Kisqali)". Food and Drug Administration. Retrieved 12 September 2017.
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  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ a b c Nasmyth K, Hunt T (1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–5. doi:10.1038/366634a0. PMID 8259207. S2CID 4270052.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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.
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Further reading

External links

Cell cycle proteins
Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)
Enzymes
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