Cyclin-dependent kinase 6
Cell division protein kinase 6 is an enzyme that in humans is encoded by the CDK6 gene.[1][2]
It is regulated by Cyclin D.
The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb.[2]
Interactions
Cyclin-dependent kinase 6 has been shown to interact with CDKN2C,[3][4][5] P16,[6][7][8] PPM1B,[9] Cyclin D3,[10][11] Cyclin D1[12][10] and PPP2CA.[9]
References
- ^ Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (Aug 1992). "A family of human cdc2-related protein kinases". EMBO J 11 (8): 2909–17. PMC 556772. PMID 1639063. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=556772.
- ^ a b "Entrez Gene: CDK6 cyclin-dependent kinase 6". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1021.
- ^ Ewing, Rob M; Chu Peter, Elisma Fred, Li Hongyan, Taylor Paul, Climie Shane, McBroom-Cerajewski Linda, Robinson Mark D, O'Connor Liam, Li Michael, Taylor Rod, Dharsee Moyez, Ho Yuen, Heilbut Adrian, Moore Lynda, Zhang Shudong, Ornatsky Olga, Bukhman Yury V, Ethier Martin, Sheng Yinglun, Vasilescu Julian, Abu-Farha Mohamed, Lambert Jean-Philippe, Duewel Henry S, Stewart Ian I, Kuehl Bonnie, Hogue Kelly, Colwill Karen, Gladwish Katharine, Muskat Brenda, Kinach Robert, Adams Sally-Lin, Moran Michael F, Morin Gregg B, Topaloglou Thodoros, Figeys Daniel (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. (England) 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1847948.
- ^ Guan, K L; Jenkins C W, Li Y, Nichols M A, Wu X, O'Keefe C L, Matera A G, Xiong Y (Dec. 1994). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes Dev. (UNITED STATES) 8 (24): 2939–52. doi:10.1101/gad.8.24.2939. ISSN 0890-9369. PMID 8001816.
- ^ Jeffrey, P D; Tong L, Pavletich N P (Dec. 2000). "Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors". Genes Dev. (UNITED STATES) 14 (24): 3115–25. doi:10.1101/gad.851100. ISSN 0890-9369. PMC 317144. PMID 11124804. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317144.
- ^ Fåhraeus, R; Paramio J M, Ball K L, Laín S, Lane D P (Jan. 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Curr. Biol. (ENGLAND) 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. ISSN 0960-9822. PMID 8805225.
- ^ Russo, A A; Tong L, Lee J O, Jeffrey P D, Pavletich N P (Sep. 1998). "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a". Nature (ENGLAND) 395 (6699): 237–43. doi:10.1038/26155. ISSN 0028-0836. PMID 9751050.
- ^ Kaldis, P; Ojala P M, Tong L, Mäkelä T P, Solomon M J (Dec. 2001). "CAK-independent activation of CDK6 by a viral cyclin". Mol. Biol. Cell (United States) 12 (12): 3987–99. ISSN 1059-1524. PMC 60770. PMID 11739795. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=60770.
- ^ a b Cheng, A; Kaldis P, Solomon M J (Nov. 2000). "Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms". J. Biol. Chem. (UNITED STATES) 275 (44): 34744–9. doi:10.1074/jbc.M006210200. ISSN 0021-9258. PMID 10934208.
- ^ a b Lin, J; Jinno S, Okayama H (Apr. 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene (England) 20 (16): 2000–9. doi:10.1038/sj.onc.1204375. ISSN 0950-9232. PMID 11360184.
- ^ Meyerson, M; Harlow E (Mar. 1994). "Identification of G1 kinase activity for cdk6, a novel cyclin D partner". Mol. Cell. Biol. (UNITED STATES) 14 (3): 2077–86. ISSN 0270-7306. PMC 358568. PMID 8114739. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=358568.
- ^ Sugimoto, M; Nakamura T, Ohtani N, Hampson L, Hampson I N, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E (Nov. 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes Dev. (UNITED STATES) 13 (22): 3027–33. doi:10.1101/gad.13.22.3027. ISSN 0890-9369. PMC 317153. PMID 10580009. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317153.
Further reading
- Adams MD, Kerlavage AR, Fleischmann RD, et al. (1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence" (PDF). Nature 377 (6547 Suppl): 3–174. PMID 7566098. http://www.columbia.edu/itc/biology/pollack/w4065/client_edit/readings/nature377_3.pdf.
- Aprelikova O, Xiong Y, Liu ET (1995). "Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase". J. Biol. Chem. 270 (31): 18195–7. doi:10.1074/jbc.270.31.18195. PMID 7629134.
- Lucas JJ, Szepesi A, Modiano JF, et al. (1995). "Regulation of synthesis and activity of the PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human T lymphocytes". J. Immunol. 154 (12): 6275–84. PMID 7759865.
- Bullrich F, MacLachlan TK, Sang N, et al. (1995). "Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer". Cancer Res. 55 (6): 1199–205. PMID 7882308.
- Guan KL, Jenkins CW, Li Y, et al. (1995). "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.
- Meyerson M, Harlow E (1994). "Identification of G1 kinase activity for cdk6, a novel cyclin D partner". Mol. Cell. Biol. 14 (3): 2077–86. PMC 358568. PMID 8114739. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=358568.
- Fåhraeus R, Paramio JM, Ball KL, et al. (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.
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Lamphere L, Fiore F, Xu X, et al. (1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368.
- Nagasawa M, Melamed I, Kupfer A, et al. (1997). "Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation". J. Immunol. 158 (11): 5146–54. PMID 9164930.
- Ezhevsky SA, Nagahara H, Vocero-Akbani AM, et al. (1997). "Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb". Proc. Natl. Acad. Sci. U.S.A. 94 (20): 10699–704. doi:10.1073/pnas.94.20.10699. PMC 23451. PMID 9380698. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=23451.
- Fåhraeus R, Laín S, Ball KL, Lane DP (1998). "Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule". Oncogene 16 (5): 587–96. doi:10.1038/sj.onc.1201580. PMID 9482104.
- Gonzales AJ, Goldsworthy TL, Fox TR (1998). "Chemical transformation of mouse liver cells results in altered cyclin D-CDK protein complexes". Carcinogenesis 19 (6): 1093–102. doi:10.1093/carcin/19.6.1093. PMID 9667749.
- Russo AA, Tong L, Lee JO, et al. (1998). "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a". Nature 395 (6699): 237–43. doi:10.1038/26155. PMID 9751050.
- Brotherton DH, Dhanaraj V, Wick S, et al. (1998). "Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d". Nature 395 (6699): 244–50. doi:10.1038/26164. PMID 9751051.
- Jiang W, Wells NJ, Hunter T (1999). "Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6". Proc. Natl. Acad. Sci. U.S.A. 96 (11): 6193–8. doi:10.1073/pnas.96.11.6193. PMC 26858. PMID 10339564. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26858.
- Yarbrough WG, Buckmire RA, Bessho M, Liu ET (1999). "Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors". J. Natl. Cancer Inst. 91 (18): 1569–74. doi:10.1093/jnci/91.18.1569. PMID 10491434.
- Harbour JW, Luo RX, Dei Santi A, et al. (1999). "Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1". Cell 98 (6): 859–69. doi:10.1016/S0092-8674(00)81519-6. PMID 10499802.
- Grossel MJ, Baker GL, Hinds PW (1999). "cdk6 can shorten G(1) phase dependent upon the N-terminal INK4 interaction domain". J. Biol. Chem. 274 (42): 29960–7. doi:10.1074/jbc.274.42.29960. PMID 10514479.
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PDB gallery
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1bi7: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX
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1bi8: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURES CDK6-P19INK4D INHIBITOR COMPLEX
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1blx: P19INK4D/CDK6 COMPLEX
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1g3n: STRUCTURE OF A P18(INK4C)-CDK6-K-CYCLIN TERNARY COMPLEX
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1jow: Crystal structure of a complex of human CDK6 and a viral cyclin
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1xo2: Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin
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2euf: X-ray structure of human CDK6-Vcyclin in complex with the inhibitor PD0332991
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2f2c: X-ray structure of human CDK6-Vcyclinwith the inhibitor aminopurvalanol
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External links
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| Cyclin |
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| CDK |
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| CDK inhibitor |
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| P53 p63 p73 family |
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Phases and
checkpoints |
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B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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