Cyclin-dependent kinase 4: Difference between revisions

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{{Infobox_gene}}
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'''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.
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Cyclin-dependent kinase 4
| HGNCid = 1773
| Symbol = CDK4
| AltSymbols =; CMM3; MGC14458; PSK-J3
| OMIM = 123829
| ECnumber = 
| Homologene = 55429
| MGIid = 88357
| GeneAtlas_image1 = PBB_GE_CDK4_202246_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004693 |text = cyclin-dependent protein kinase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0000307 |text = cyclin-dependent protein kinase holoenzyme complex}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005667 |text = transcription factor complex}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0000082 |text = G1/S transition of mitotic cell cycle}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0051301 |text = cell division}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1019
    | Hs_Ensembl = ENSG00000135446
    | Hs_RefseqProtein = NP_000066
    | Hs_RefseqmRNA = NM_000075
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 56428272
    | Hs_GenLoc_end = 56432431
    | Hs_Uniprot = P11802
    | Mm_EntrezGene = 12567
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_009870
    | Mm_RefseqProtein = NP_034000
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot =
  }}
}}
'''Cyclin-dependent kinase 4''' is part of the [[cyclin-dependent kinase]] family.


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
The protein encoded by this gene is a member of the [[Serine/threonine-specific protein kinase|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 (gene)|p16<sup>INK4a</sup>]]. This kinase was shown to be responsible for the phosphorylation of [[retinoblastoma gene]] product ([[Retinoblastoma protein|Rb]]).<ref name = "entrez"/> Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the [[Retinoblastoma protein|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.<ref>{{Cite web|url=http://www.uniprot.org/uniprot/P11802|title=|date=|website=|publisher=|access-date=}}</ref>
{{PBB_Summary
 
| section_title =
== Clinical significance ==
| summary_text = 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). 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.<ref>{{cite web | title = Entrez Gene: CDK4 cyclin-dependent kinase 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1019| accessdate = }}</ref>
 
}}
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.<ref name = "entrez">{{cite web | title = Entrez Gene: CDK4 cyclin-dependent kinase 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1019| accessdate = }}</ref>


It is regulated by [[Cyclin D]].
It is regulated by [[Cyclin D]].
===Inhibitors===
[[Palbociclib]] and [[Ribociclib]] are [[US FDA]] approved  CDK4 and CDK6 inhibitors for the treatment of [[estrogen receptor]] positive/ [[HER2]] negative advanced breast cancer.<ref>{{cite web|title=Approved Drugs > Ribociclib (Kisqali)|url=https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546438.htm|accessdate=12 September 2017}}</ref>
See also [[CDK inhibitor]] for inhibitors of various CDKs.
==Interactions==
Cyclin-dependent kinase 4 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CDC37]],<ref name = pmid17353931>{{cite journal |vauthors=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 | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue = 1| pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134}}</ref><ref name = pmid8703009>{{cite journal |vauthors=Dai K, Kobayashi R, Beach D | title = Physical interaction of mammalian CDC37 with CDK4 | journal = J. Biol. Chem. | volume = 271 | issue = 36 | pages = 22030–4 | year = 1996 | pmid = 8703009 | doi = 10.1074/jbc.271.36.22030}}</ref><ref name = pmid9150368>{{cite journal |vauthors=Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J | title = Interaction between Cdc37 and Cdk4 in human cells | journal = Oncogene | volume = 14 | issue = 16 | pages = 1999–2004 | year = 1997 | pmid = 9150368 | doi = 10.1038/sj.onc.1201036}}</ref><ref name = pmid8666233>{{cite journal |vauthors=Stepanova L, Leng X, Parker SB, Harper JW | title = Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 | journal = Genes Dev. | volume = 10 | issue = 12 | pages = 1491–502 | year = 1996 | pmid = 8666233 | doi = 10.1101/gad.10.12.1491}}</ref>
* [[CDKN1B]],<ref name = pmid11360184/><ref name = pmid10908655/>
* [[CDKN2B]],<ref name = pmid16189514/><ref name = pmid16169070>{{cite journal | pmid = |vauthors=Ghavidel A, Cagney G, Emili A | title = A skeleton of the human protein interactome | journal = Cell | volume = 122 | issue = 6 | pages = 830–2 | year = 2005 | doi = 10.1016/j.cell.2005.09.006}}</ref>
* [[CDKN2C]],<ref name = pmid17353931/><ref name = pmid8001816>{{cite journal |vauthors=Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y | title = Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function | journal = Genes Dev. | volume = 8 | issue = 24 | pages = 2939–52 | year = 1994 | pmid = 8001816 | doi = 10.1101/gad.8.24.2939}}</ref>
* [[CEBPA]],<ref name = pmid11684017>{{cite journal |vauthors=Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA | title = C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 | journal = Mol. Cell | volume = 8 | issue = 4 | pages = 817–28 | year = 2001 | pmid = 11684017 | doi = 10.1016/S1097-2765(01)00366-5}}</ref>
* [[Cyclin D1|CCND1]],<ref name = pmid11360184/><ref name = pmid10908655>{{cite journal |vauthors=Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM | title = Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 16 | pages = 9042–6 | year = 2000 | pmid = 10908655 | pmc = 16818 | doi = 10.1073/pnas.160016897}}</ref><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9837900>{{cite journal |vauthors=Taulés M, Rius E, Talaya D, López-Girona A, Bachs O, Agell N | title = Calmodulin is essential for cyclin-dependent kinase 4 (Cdk4) activity and nuclear accumulation of cyclin D1-Cdk4 during G1 | journal = J. Biol. Chem. | volume = 273 | issue = 50 | pages = 33279–86 | year = 1998 | pmid = 9837900 | doi = 10.1074/jbc.273.50.33279}}</ref><ref name = pmid9228064>{{cite journal |vauthors=Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = J. Biol. Chem. | volume = 272 | issue = 30 | pages = 18869–74 | year = 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869}}</ref>
* [[Cyclin D3|CCND3]],<ref name = pmid11360184>{{cite journal |vauthors=Lin J, Jinno S, Okayama H | title = Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence | journal = Oncogene | volume = 20 | issue = 16 | pages = 2000–9 | year = 2001 | pmid = 11360184 | doi = 10.1038/sj.onc.1204375}}</ref><ref name = pmid16189514>{{cite journal |vauthors=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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209}}</ref><ref name = pmid14641107>{{cite journal |vauthors=Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I | title = A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 | journal = Biochem. J. | volume = 378 | issue = Pt 2 | pages = 673–9 | year = 2004 | pmid = 14641107 | pmc = 1223988 | doi = 10.1042/BJ20031765}}</ref><ref name = pmid10342870>{{cite journal |vauthors=Zhang Q, Wang X, Wolgemuth DJ | title = Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis | journal = Endocrinology | volume = 140 | issue = 6 | pages = 2790–800 | year = 1999 | pmid = 10342870 | doi = 10.1210/endo.140.6.6756}}</ref>
* [[Drebrin-like|DBNL]],<ref name = pmid17353931/>
* [[MyoD]],<ref name = pmid10601020>{{cite journal |vauthors=Zhang JM, Zhao X, Wei Q, Paterson BM | title = Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation | journal = EMBO J. | volume = 18 | issue = 24 | pages = 6983–93 | year = 1999 | pmid = 10601020 | pmc = 1171761 | doi = 10.1093/emboj/18.24.6983}}</ref><ref name = pmid10022835>{{cite journal |vauthors=Zhang JM, Wei Q, Zhao X, Paterson BM | title = Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 | journal = EMBO J. | volume = 18 | issue = 4 | pages = 926–33 | year = 1999 | pmid = 10022835 | pmc = 1171185 | doi = 10.1093/emboj/18.4.926}}</ref>
* [[P16 (gene)|P16]],<ref name = pmid17353931/><ref name = pmid10580009/><ref name = pmid8259215/><ref name = pmid9228064/><ref name = pmid8805225>{{cite journal |vauthors=Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP | title = Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A | journal = Curr. Biol. | volume = 6 | issue = 1 | pages = 84–91 | year = 1996 | pmid = 8805225 | doi = 10.1016/S0960-9822(02)00425-6}}</ref><ref name = pmid15065884/>
* [[PCNA]],<ref name = pmid8259215>{{cite journal | pmid = 8259207|vauthors=Nasmyth K, Hunt T | title = Cell cycle. Dams and sluices | journal = Nature | volume = 366 | issue = 6456 | pages = 634–5 | year = 1993 | doi = 10.1038/366634a0}}</ref><ref name = pmid8101826>{{cite journal |vauthors=Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes Dev. | volume = 7 | issue = 8 | pages = 1572–83 | year = 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572}}</ref>  and
* [[SERTAD1]].<ref name = pmid10580009>{{cite journal |vauthors=Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes Dev. | volume = 13 | issue = 22 | pages = 3027–33 | year = 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027}}</ref><ref name = pmid15065884>{{cite journal |vauthors=Li J, Melvin WS, Tsai MD, Muscarella P | title = The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner | journal = Biochemistry | volume = 43 | issue = 14 | pages = 4394–9 | year = 2004 | pmid = 15065884 | doi = 10.1021/bi035601s}}</ref>
{{Div col end}}
[[Image:Signal transduction pathways.svg|300px|thumb|left|Overview of signal transduction pathways involved in [[apoptosis]]. (CDK4 in the (pink) nucleus)]]
{{Clear}}


==References==
==References==
{{reflist|2}}
{{reflist|colwidth=35em}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|colwidth=35em}}
{{PBB_Further_reading
*{{cite journal  | author=Hanks SK |title=Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 2 |pages= 388–92 |year= 1987 |pmid= 2948189 |doi=10.1073/pnas.84.2.388  | pmc=304212 }}
| citations =
*{{cite journal |title=Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins |journal=Oncogene |volume=11 |issue= 8 |pages= 1581–8 |year= 1995 |pmid= 7478582 |doi= |author1=Hall M |author2=Bates S |author3=Peters G |name-list-format=vanc  }}
*{{cite journal  | author=Hanks SK |title=Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 2 |pages= 388-92 |year= 1987 |pmid= 2948189 |doi=  }}
*{{cite journal |title=Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 19 |pages= 8871–5 |year= 1995 |pmid= 7568034 |doi=10.1073/pnas.92.19.8871 |display-authors=3 |author1=Tassan JP |author2=Jaquenoud M |author3=Léopold P |name-list-format=vanc |last4=Schultz |first4=SJ |last5=Nigg |first5=EA |pmc=41069  }}
*{{cite journal | author=Hall M, Bates S, Peters G |title=Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. |journal=Oncogene |volume=11 |issue= 8 |pages= 1581-8 |year= 1995 |pmid= 7478582 |doi= }}
*{{cite journal |title=Mapping of gene loci in the Q13-Q15 region of chromosome 12 |journal=Chromosome Res. |volume=3 |issue= 4 |pages= 261–2 |year= 1995 |pmid= 7606365 |doi=10.1007/BF00713052 |display-authors=3 |author1=Mitchell EL |author2=White GR |author3=Santibanez-Koref MF |name-list-format=vanc |last4=Varley |first4=JM |last5=Heighway |first5=J }}
*{{cite journal  | author=Tassan JP, Jaquenoud M, Léopold P, ''et al.'' |title=Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 19 |pages= 8871-5 |year= 1995 |pmid= 7568034 |doi= }}
*{{cite journal |title=A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma |journal=Science |volume=269 |issue= 5228 |pages= 1281–4 |year= 1995 |pmid= 7652577 |doi=10.1126/science.7652577 |display-authors=3 |author1=Wölfel T |author2=Hauer M |author3=Schneider J |name-list-format=vanc |last4=Serrano |first4=M |last5=Wölfel |first5=C |last6=Klehmann-hieb |first6=E |last7=De Plaen |first7=E |last8=Hankeln |first8=T |last9=Meyer Zum Büschenfelde |first9=KH  }}
*{{cite journal  | author=Mitchell EL, White GR, Santibanez-Koref MF, ''et al.'' |title=Mapping of gene loci in the Q13-Q15 region of chromosome 12. |journal=Chromosome Res. |volume=3 |issue= 4 |pages= 261-2 |year= 1995 |pmid= 7606365 |doi= }}
*{{cite journal |title=Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2672–81 |year= 1995 |pmid= 7739547 |doi= |display-authors=3 |author1=Hirai H |author2=Roussel MF |author3=Kato JY |name-list-format=vanc |last4=Ashmun |first4=RA |last5=Sherr |first5=CJ |pmc=230497  }}
*{{cite journal  | author=Wölfel T, Hauer M, Schneider J, ''et al.'' |title=A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. |journal=Science |volume=269 |issue= 5228 |pages= 1281-4 |year= 1995 |pmid= 7652577 |doi=  }}
*{{cite journal |title=Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4 |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2682–8 |year= 1995 |pmid= 7739548 |doi= |display-authors=3 |author1=Chan FK |author2=Zhang J |author3=Cheng L |name-list-format=vanc |last4=Shapiro |first4=DN |last5=Winoto |first5=A |pmc=230498  }}
*{{cite journal | author=Hirai H, Roussel MF, Kato JY, ''et al.'' |title=Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2672-81 |year= 1995 |pmid= 7739547 |doi= }}
*{{cite journal |title=Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function |journal=Genes Dev. |volume=8 |issue= 24 |pages= 2939–52 |year= 1995 |pmid= 8001816 |doi=10.1101/gad.8.24.2939 |display-authors=3 |author1=Guan KL |author2=Jenkins CW |author3=Li Y |name-list-format=vanc |last4=Nichols |first4=MA |last5=Wu |first5=X |last6=O'Keefe |first6=CL |last7=Matera |first7=AG |last8=Xiong |first8=Y }}
*{{cite journal  | author=Chan FK, Zhang J, Cheng L, ''et al.'' |title=Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. |journal=Mol. Cell. Biol. |volume=15 |issue= 5 |pages= 2682-8 |year= 1995 |pmid= 7739548 |doi= }}
*{{cite journal |title=Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase |journal=Mol. Cell. Biol. |volume=14 |issue= 4 |pages= 2713–21 |year= 1994 |pmid= 8139570 |doi= 10.1128/MCB.14.4.2713|author1=Kato JY |author2=Matsuoka M |author3=Strom DK |author4=Sherr CJ |name-list-format=vanc |pmc=358637}}
*{{cite journal  | author=Guan KL, Jenkins CW, Li Y, ''et al.'' |title=Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. |journal=Genes Dev. |volume=8 |issue= 24 |pages= 2939-52 |year= 1995 |pmid= 8001816 |doi=  }}
*{{cite journal |title=Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas |journal=Cancer Res. |volume=53 |issue= 22 |pages= 5535–41 |year= 1993 |pmid= 8221695 |doi= |display-authors=3 |author1=Khatib ZA |author2=Matsushime H |author3=Valentine M |name-list-format=vanc |last4=Shapiro |first4=DN |last5=Sherr |first5=CJ |last6=Look |first6=AT }}
*{{cite journal | author=Kato JY, Matsuoka M, Strom DK, Sherr CJ |title=Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. |journal=Mol. Cell. Biol. |volume=14 |issue= 4 |pages= 2713-21 |year= 1994 |pmid= 8139570 |doi= }}
*{{cite journal |title=A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 |journal=Nature |volume=366 |issue= 6456 |pages= 704–7 |year= 1994 |pmid= 8259215 |doi= 10.1038/366704a0 |author1=Serrano M |author2=Hannon GJ |author3=Beach D |name-list-format=vanc }}
*{{cite journal  | author=Khatib ZA, Matsushime H, Valentine M, ''et al.'' |title=Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. |journal=Cancer Res. |volume=53 |issue= 22 |pages= 5535-41 |year= 1993 |pmid= 8221695 |doi=  }}
*{{cite journal |title=Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes |journal=Cytogenet. Cell Genet. |volume=66 |issue= 1 |pages= 72–4 |year= 1994 |pmid= 8275715 |doi=10.1159/000133669 |author1=Demetrick DJ |author2=Zhang H |author3=Beach DH |name-list-format=vanc }}
*{{cite journal | author=Serrano M, Hannon GJ, Beach D |title=A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. |journal=Nature |volume=366 |issue= 6456 |pages= 704-7 |year= 1994 |pmid= 8259215 |doi= 10.1038/366704a0 }}
*{{cite journal |title=Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4 |journal=Genes Dev. |volume=7 |issue= 3 |pages= 331–42 |year= 1993 |pmid= 8449399 |doi=10.1101/gad.7.3.331 |display-authors=3 |author1=Kato J |author2=Matsushime H |author3=Hiebert SW |name-list-format=vanc |last4=Ewen |first4=ME |last5=Sherr |first5=CJ  }}
*{{cite journal | author=Demetrick DJ, Zhang H, Beach DH |title=Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. |journal=Cytogenet. Cell Genet. |volume=66 |issue= 1 |pages= 72-4 |year= 1994 |pmid= 8275715 |doi= }}
*{{cite journal |title=Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma |journal=Nat. Genet. |volume=12 |issue= 1 |pages= 97–9 |year= 1996 |pmid= 8528263 |doi= 10.1038/ng0196-97 |display-authors=3 |author1=Zuo L |author2=Weger J |author3=Yang Q |name-list-format=vanc |last4=Goldstein |first4=AM |last5=Tucker |first5=MA |last6=Walker |first6=GJ |last7=Hayward |first7=N |last8=Dracopoli |first8=NC }}
*{{cite journal  | author=Kato J, Matsushime H, Hiebert SW, ''et al.'' |title=Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. |journal=Genes Dev. |volume=7 |issue= 3 |pages= 331-42 |year= 1993 |pmid= 8449399 |doi=  }}
*{{cite journal |title=A "double adaptor" method for improved shotgun library construction |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107–13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 |display-authors=3 |author1=Andersson B |author2=Wentland MA |author3=Ricafrente JY |name-list-format=vanc |last4=Liu |first4=W |last5=Gibbs |first5=RA }}
*{{cite journal | author=Zuo L, Weger J, Yang Q, ''et al.'' |title=Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. |journal=Nat. Genet. |volume=12 |issue= 1 |pages= 97-9 |year= 1996 |pmid= 8528263 |doi= 10.1038/ng0196-97 }}
*{{cite journal |title=Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites |journal=J. Biol. Chem. |volume=271 |issue= 14 |pages= 8313–20 |year= 1996 |pmid= 8626527 |doi=10.1074/jbc.271.14.8313 |author1=Knudsen ES |author2=Wang JY |name-list-format=vanc  }}
*{{cite journal  | author=Andersson B, Wentland MA, Ricafrente JY, ''et al.'' |title=A "double adaptor" method for improved shotgun library construction. |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107-13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 }}
*{{cite journal |title=Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage |journal=J. Biol. Chem. |volume=271 |issue= 22 |pages= 13283–91 |year= 1996 |pmid= 8662825 |doi=10.1074/jbc.271.22.13283 |author1=Poon RY |author2=Jiang W |author3=Toyoshima H |author4=Hunter T |name-list-format=vanc  }}
*{{cite journal  | author=Knudsen ES, Wang JY |title=Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites. |journal=J. Biol. Chem. |volume=271 |issue= 14 |pages= 8313-20 |year= 1996 |pmid= 8626527 |doi=  }}
*{{cite journal |title=Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 |journal=Genes Dev. |volume=10 |issue= 12 |pages= 1491–502 |year= 1996 |pmid= 8666233 |doi=10.1101/gad.10.12.1491 |author1=Stepanova L |author2=Leng X |author3=Parker SB |author4=Harper JW |name-list-format=vanc  }}
*{{cite journal | author=Poon RY, Jiang W, Toyoshima H, Hunter T |title=Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage. |journal=J. Biol. Chem. |volume=271 |issue= 22 |pages= 13283-91 |year= 1996 |pmid= 8662825 |doi= }}
*{{cite journal |title=Physical interaction of mammalian CDC37 with CDK4 |journal=J. Biol. Chem. |volume=271 |issue= 36 |pages= 22030–4 |year= 1996 |pmid= 8703009 |doi=10.1074/jbc.271.36.22030 |author1=Dai K |author2=Kobayashi R |author3=Beach D |name-list-format=vanc  }}
*{{cite journal | author=Stepanova L, Leng X, Parker SB, Harper JW |title=Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. |journal=Genes Dev. |volume=10 |issue= 12 |pages= 1491-502 |year= 1996 |pmid= 8666233 |doi=  }}
*{{cite journal |title=Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A |journal=Curr. Biol. |volume=6 |issue= 1 |pages= 84–91 |year= 1996 |pmid= 8805225 |doi=10.1016/S0960-9822(02)00425-6 |display-authors=3 |author1=Fåhraeus R |author2=Paramio JM |author3=Ball KL |name-list-format=vanc |last4=Laín |first4=S |last5=Lane |first5=DP }}
*{{cite journal | author=Dai K, Kobayashi R, Beach D |title=Physical interaction of mammalian CDC37 with CDK4. |journal=J. Biol. Chem. |volume=271 |issue= 36 |pages= 22030-4 |year= 1996 |pmid= 8703009 |doi= }}
*{{cite journal  | author=Fåhraeus R, Paramio JM, Ball KL, ''et al.'' |title=Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A. |journal=Curr. Biol. |volume=6 |issue= 1 |pages= 84-91 |year= 1996 |pmid= 8805225 |doi=  }}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* {{MeshName|Cyclin-Dependent+Kinase+4}}
* {{MeshName|Cyclin-Dependent+Kinase+4}}
* {{UCSC genome browser|CDK4}}
* {{UCSC gene details|CDK4}}


{{transferase-stub}}
{{Cell cycle proteins}}
{{Cell cycle proteins}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


{{DEFAULTSORT:Cyclin-dependent kinase 04}}
[[Category:Cell cycle]]
[[Category:Cell cycle]]
[[Category:Proteins]]
[[Category:Proteins]]
[[Category:EC 2.7.11]]
[[Category:Oncogenes]]

Revision as of 17:43, 5 December 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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View/Edit Human

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 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

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

Palbociclib and Ribociclib are US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative advanced breast cancer.[3]

See also CDK inhibitor for inhibitors of various CDKs.

Interactions

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

File:Signal transduction pathways.svg
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".
  2. ↑ http://www.uniprot.org/uniprot/P11802. Missing or empty |title= (help)
  3. ↑ "Approved Drugs > Ribociclib (Kisqali)". Retrieved 12 September 2017.
  4. ↑ 4.0 4.1 4.2 4.3 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.
  5. ↑ Dai K, Kobayashi R, Beach D (1996). "Physical interaction of mammalian CDC37 with CDK4". J. Biol. Chem. 271 (36): 22030–4. doi:10.1074/jbc.271.36.22030. PMID 8703009.
  6. ↑ Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J (1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368.
  7. ↑ Stepanova L, Leng X, Parker SB, Harper JW (1996). "Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4". Genes Dev. 10 (12): 1491–502. doi:10.1101/gad.10.12.1491. PMID 8666233.
  8. ↑ 8.0 8.1 8.2 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.
  9. ↑ 9.0 9.1 Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM (2000). "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. doi:10.1073/pnas.160016897. PMC 16818. PMID 10908655.
  10. ↑ 10.0 10.1 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 (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
  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. ↑ 14.0 14.1 14.2 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. ↑ 15.0 15.1 15.2 Nasmyth K, Hunt T (1993). "Cell cycle. Dams and sluices". Nature. 366 (6456): 634–5. doi:10.1038/366634a0. PMID 8259207.
  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. ↑ 17.0 17.1 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. ↑ 23.0 23.1 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.
  24. ↑ Xiong Y, Zhang H, Beach D (1993). "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes Dev. 7 (8): 1572–83. doi:10.1101/gad.7.8.1572. PMID 8101826.

Further reading

External links

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