Cyclin-dependent kinase 4

CDK4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2W96, 2W99, 2W9F, 2W9Z, 3G33, 5FWL, 5FWM, 5FWK
Identifiers
Aliases	CDK4, CMM3, PSK-J3, cyclin-dependent kinase 4, cyclin dependent kinase 4
External IDs	OMIM: 123829; MGI: 88357; HomoloGene: 55429; GeneCards: CDK4; OMA:CDK4 - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	57,756,013 bp
RNA expression pattern
	Top expressed in
	ganglionic eminence; ; ventricular zone; ; stromal cell of endometrium; ; right adrenal gland; ; right ovary; ; smooth muscle tissue; ; right adrenal cortex; ; left ovary; ; left adrenal gland; ; left adrenal cortex;
	n/a
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; protein kinase activity; kinase activity; protein serine/threonine kinase activity; cyclin-dependent protein serine/threonine kinase regulator activity; protein binding; ATP binding; cyclin binding; cyclin-dependent protein serine/threonine kinase activity; protein-containing complex binding;
Cellular component	cytoplasm; cytosol; cyclin-dependent protein kinase holoenzyme complex; nuclear membrane; membrane; transcription regulator complex; bicellular tight junction; nucleoplasm; nucleolus; perinuclear region of cytoplasm; chromatin; nucleus; cyclin D2-CDK4 complex; protein-containing complex;
Biological process	phosphorylation; response to testosterone; positive regulation of fibroblast proliferation; response to hyperoxia; positive regulation of translation; regulation of cell cycle; cell division; protein phosphorylation; lens development in camera-type eye; regulation of cell population proliferation; response to lead ion; circadian rhythm; animal organ regeneration; positive regulation of cell population proliferation; positive regulation of cell size; positive regulation of apoptotic process; regulation of gene expression; cell cycle; positive regulation of G2/M transition of mitotic cell cycle; response to toxic substance; positive regulation of cell cycle; signal transduction; multicellular organism development; response to organic substance; cellular response to insulin stimulus; regulation of multicellular organism growth; regulation of insulin receptor signaling pathway; regulation of lipid biosynthetic process; regulation of lipid catabolic process; adipose tissue development; cellular response to lipopolysaccharide; cellular response to interleukin-4; cellular response to phorbol 13-acetate 12-myristate; cellular response to ionomycin; transcription initiation from RNA polymerase II promoter; G1/S transition of mitotic cell cycle; regulation of cyclin-dependent protein serine/threonine kinase activity; negative regulation of G1/S transition of mitotic cell cycle;
	Sources:Amigo / QuickGO
Orthologs
	1019
	12567
	ENSG00000135446
	n/a
	P11802
	P30285
	NM_052984; NM_000075
	NM_009870; NM_001355005
	NP_000066
	NP_034000; NP_001341934
	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

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).^[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, 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.^[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:

CDC37,^[9]^[10]^[11]^[12]
CDKN1B,^[13]^[14]
CDKN2B,^[15]^[16]
CDKN2C,^[9]^[17]
CEBPA,^[18]
CCND1,^[13]^[14]^[19]^[20]^[21]^[22]
CCND3,^[13]^[15]^[23]^[24]
DBNL,^[9]
MyoD,^[25]^[26]
P16,^[9]^[19]^[20]^[22]^[27]^[28]
PCNA,^[20]^[29] and
SERTAD1.^[19]^[28]

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

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000135446 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: CDK4 cyclin-dependent kinase 4".
^ "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein".
^ Sheppard KE, McArthur GA (October 2013). "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. PMID 24089445. S2CID 12933349.
^ Sobhani N, D'Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, et al. (April 2019). "Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer". Cells. 8 (4): 321. doi:10.3390/cells8040321. PMC 6523967. PMID 30959874.
^ "Approved Drugs > Ribociclib (Kisqali)". Food and Drug Administration. Retrieved 12 September 2017.
^ ^a ^b ^c ^d Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
^ Dai K, Kobayashi R, Beach D (September 1996). "Physical interaction of mammalian CDC37 with CDK4". The Journal of Biological Chemistry. 271 (36): 22030–22034. doi:10.1074/jbc.271.36.22030. PMID 8703009.
^ Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, et al. (April 1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368. S2CID 25236893.
^ Stepanova L, Leng X, Parker SB, Harper JW (June 1996). "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes & Development. 10 (12): 1491–1502. doi:10.1101/gad.10.12.1491. PMID 8666233.
^ ^a ^b ^c Lin J, Jinno S, Okayama H (April 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene. 20 (16): 2000–2009. doi:10.1038/sj.onc.1204375. PMID 11360184. S2CID 25204152.
^ ^a ^b Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (August 2000). "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. Bibcode:2000PNAS...97.9042C. doi:10.1073/pnas.160016897. PMC 16818. PMID 10908655.
^ ^a ^b Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
^ Ghavidel A, Cagney G, Emili A (September 2005). "A skeleton of the human protein interactome". Cell. 122 (6): 830–832. doi:10.1016/j.cell.2005.09.006. PMID 16179252. S2CID 7410135.
^ Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, et al. (December 1994). "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. doi:10.1101/gad.8.24.2939. PMID 8001816.
^ Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, et al. (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Molecular Cell. 8 (4): 817–828. doi:10.1016/S1097-2765(01)00366-5. PMID 11684017.
^ ^a ^b ^c Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, et al. (November 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development. 13 (22): 3027–3033. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009.
^ ^a ^b ^c Nasmyth K, Hunt T (December 1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–635. doi:10.1038/366634a0. PMID 8259207. S2CID 4270052.
^ Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N (December 1998). "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. doi:10.1074/jbc.273.50.33279. PMID 9837900.
^ ^a ^b Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, et al. (July 1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". The Journal of Biological Chemistry. 272 (30): 18869–18874. doi:10.1074/jbc.272.30.18869. PMID 9228064.
^ Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I (March 2004). "A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95". The Biochemical Journal. 378 (Pt 2): 673–679. doi:10.1042/BJ20031765. PMC 1223988. PMID 14641107.
^ Zhang Q, Wang X, Wolgemuth DJ (June 1999). "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology. 140 (6): 2790–2800. doi:10.1210/endo.140.6.6756. PMID 10342870. S2CID 45094232.
^ Zhang JM, Zhao X, Wei Q, Paterson BM (December 1999). "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. doi:10.1093/emboj/18.24.6983. PMC 1171761. PMID 10601020.
^ Zhang JM, Wei Q, Zhao X, Paterson BM (February 1999). "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". The EMBO Journal. 18 (4): 926–933. doi:10.1093/emboj/18.4.926. PMC 1171185. PMID 10022835.
^ Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (January 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Current Biology. 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. hdl:20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9. PMID 8805225. S2CID 23024663.
^ ^a ^b Li J, Melvin WS, Tsai MD, Muscarella P (April 2004). "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry. 43 (14): 4394–4399. CiteSeerX 10.1.1.386.140. doi:10.1021/bi035601s. PMID 15065884.
^ Xiong Y, Zhang H, Beach D (August 1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes & Development. 7 (8): 1572–1583. doi:10.1101/gad.7.8.1572. PMID 8101826.

External links

Cyclin-Dependent+Kinase+4 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
CDK4 human gene location in the UCSC Genome Browser.
CDK4 human gene details in the UCSC Genome Browser.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000135446 – Ensembl, May 2017

[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.

[entrez-4] "Entrez Gene: CDK4 cyclin-dependent kinase 4".

[5] "CDK4 - Cyclin-dependent kinase 4 - Homo sapiens (Human) - CDK4 gene & protein".

[6] Sheppard KE, McArthur GA (October 2013). "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. PMID 24089445. S2CID 12933349.

[7] Sobhani N, D'Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, et al. (April 2019). "Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer". Cells. 8 (4): 321. doi:10.3390/cells8040321. PMC 6523967. PMID 30959874.

[8] "Approved Drugs > Ribociclib (Kisqali)". Food and Drug Administration. Retrieved 12 September 2017.

[pmid17353931-9] Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

[pmid8703009-10] Dai K, Kobayashi R, Beach D (September 1996). "Physical interaction of mammalian CDC37 with CDK4". The Journal of Biological Chemistry. 271 (36): 22030–22034. doi:10.1074/jbc.271.36.22030. PMID 8703009.

[pmid9150368-11] Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, et al. (April 1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368. S2CID 25236893.

[pmid8666233-12] Stepanova L, Leng X, Parker SB, Harper JW (June 1996). "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes & Development. 10 (12): 1491–1502. doi:10.1101/gad.10.12.1491. PMID 8666233.

[pmid11360184-13] Lin J, Jinno S, Okayama H (April 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene. 20 (16): 2000–2009. doi:10.1038/sj.onc.1204375. PMID 11360184. S2CID 25204152.

[pmid10908655-14] Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (August 2000). "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. Bibcode:2000PNAS...97.9042C. doi:10.1073/pnas.160016897. PMC 16818. PMID 10908655.

[pmid16189514-15] Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.

[pmid16169070-16] Ghavidel A, Cagney G, Emili A (September 2005). "A skeleton of the human protein interactome". Cell. 122 (6): 830–832. doi:10.1016/j.cell.2005.09.006. PMID 16179252. S2CID 7410135.

[pmid8001816-17] Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, et al. (December 1994). "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. doi:10.1101/gad.8.24.2939. PMID 8001816.

[pmid11684017-18] Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, et al. (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Molecular Cell. 8 (4): 817–828. doi:10.1016/S1097-2765(01)00366-5. PMID 11684017.

[pmid10580009-19] Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, et al. (November 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development. 13 (22): 3027–3033. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009.

[pmid8259215-20] Nasmyth K, Hunt T (December 1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–635. doi:10.1038/366634a0. PMID 8259207. S2CID 4270052.

[pmid9837900-21] Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N (December 1998). "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. doi:10.1074/jbc.273.50.33279. PMID 9837900.

[pmid9228064-22] Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, et al. (July 1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". The Journal of Biological Chemistry. 272 (30): 18869–18874. doi:10.1074/jbc.272.30.18869. PMID 9228064.

[pmid14641107-23] Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I (March 2004). "A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95". The Biochemical Journal. 378 (Pt 2): 673–679. doi:10.1042/BJ20031765. PMC 1223988. PMID 14641107.

[pmid10342870-24] Zhang Q, Wang X, Wolgemuth DJ (June 1999). "Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis". Endocrinology. 140 (6): 2790–2800. doi:10.1210/endo.140.6.6756. PMID 10342870. S2CID 45094232.

[pmid10601020-25] Zhang JM, Zhao X, Wei Q, Paterson BM (December 1999). "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. doi:10.1093/emboj/18.24.6983. PMC 1171761. PMID 10601020.

[pmid10022835-26] Zhang JM, Wei Q, Zhao X, Paterson BM (February 1999). "Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4". The EMBO Journal. 18 (4): 926–933. doi:10.1093/emboj/18.4.926. PMC 1171185. PMID 10022835.

[pmid8805225-27] Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (January 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Current Biology. 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. hdl:20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9. PMID 8805225. S2CID 23024663.

[pmid15065884-28] Li J, Melvin WS, Tsai MD, Muscarella P (April 2004). "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry. 43 (14): 4394–4399. CiteSeerX 10.1.1.386.140. doi:10.1021/bi035601s. PMID 15065884.

[pmid8101826-29] Xiong Y, Zhang H, Beach D (August 1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes & Development. 7 (8): 1572–1583. doi:10.1101/gad.7.8.1572. PMID 8101826.

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