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Gene Review

CDK6  -  cyclin-dependent kinase 6

Homo sapiens

Synonyms: CDKN6, Cell division protein kinase 6, Cyclin-dependent kinase 6, MCPH12, PLSTIRE, ...
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Disease relevance of CDK6


High impact information on CDK6

  • The point in G1 at which cells irrevocably commit to DNA synthesis is controlled by protein complexes consisting of cyclin-dependent kinases (CDK4 or CDK6) and cyclins (D1, D2 or D3) [6].
  • The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d protein has been determined at 1.9 A resolution [7].
  • Here we present the 2.9-A crystal structure of the inactive ternary complex between Cdk6, the INK4 inhibitor p18(INK4c), and a D-type viral cyclin [8].
  • Recombinant p18 inhibits the kinase activity of cyclin D-CDK6 [9].
  • Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest [10].

Chemical compound and disease context of CDK6


Biological context of CDK6

  • CDK6 is present in the chromatin structure of these cells in association with the AR and the promoter region of the prostate-specific antigen gene [1].
  • The D-type cyclins and their major kinase partners CDK4 and CDK6 regulate G0-G1-S progression by contributing to the phosphorylation and inactivation of the retinoblastoma gene product, pRB [16].
  • The regulation of the D-type cyclin-dependent kinase (CDK4 and CDK6) activity appears to be the key step in the progression of eukaryotic cells through the G1 cell cycle phase [17].
  • Our findings suggest that during the cell division cycle the members of the p16(INK4) protein family and cyclin Ds compete for binding to CDK4/CDK6 and that their quantitative ratio is essential for G1 --> S transition [17].
  • In cells, expression of CDK6 or to a lesser degree of a nonphosphorylatable CDK6(T177A) together with KSHV-cyclin induced apoptosis, indicating that CDK6 activation by KSHV-cyclin can proceed in the absence of phosphorylation by CAK in vivo [18].

Anatomical context of CDK6


Associations of CDK6 with chemical compounds

  • Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding [22].
  • We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin [22].
  • Expression of CDK6 and beta-actin was not affected by LY-294002 [23].
  • Substitution of aspartic acid 92 by alanine instead increases the binding of the peptide to cdk4 and cdk6 and the kinase inhibitory activity [24].
  • Substitution of two valine residues corresponding to amino acids 95 and 96 (V95A and V96A) of the p16 peptide reduces the binding to cdk4 and cdk6 and increases its IC0.5 for kinase inhibition approximately threefold when linked to the Antennapedia homeodomain carrier sequence [24].

Physical interactions of CDK6


Enzymatic interactions of CDK6


Regulatory relationships of CDK6

  • This effect of CDK6 does not require its kinase activity and is inhibited by cyclin D1 and p16INK4a [1].
  • These findings suggest that CDK6 may play an important role in the development and/or progression of a subset of human prostate cancers by stimulating the activity of the AR [1].
  • I3C selectively inhibited the expression of CDK6 protein and transcripts and strongly stimulated the production of the p16 CDK inhibitor [30].
  • In contrast, Cdk4 was expressed at high levels in several tumor cell lines and Cdk6 was ectopically expressed in two sarcoma lines, suggesting a possible involvement of these two Cdks in oncogenesis [31].
  • Thus, expression of the viral cyclin enables cells to subvert the cell cycle inhibitory function of p21Cip1 by promoting cdk6-dependent phosphorylation of this antiproliferative protein [14].

Other interactions of CDK6


Analytical, diagnostic and therapeutic context of CDK6


  1. Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Lim, J.T., Mansukhani, M., Weinstein, I.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Structural basis for CDK6 activation by a virus-encoded cyclin. Schulze-Gahmen, U., Kim, S.H. Nat. Struct. Biol. (2002) [Pubmed]
  3. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Li, Y., Nichols, M.A., Shay, J.W., Xiong, Y. Cancer Res. (1994) [Pubmed]
  4. Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma. Easton, J., Wei, T., Lahti, J.M., Kidd, V.J. Cancer Res. (1998) [Pubmed]
  5. Up-regulation of cyclin-dependent kinase 4/cyclin D2 expression but down-regulation of cyclin-dependent kinase 2/cyclin E in testicular germ cell tumors. Schmidt, B.A., Rose, A., Steinhoff, C., Strohmeyer, T., Hartmann, M., Ackermann, R. Cancer Res. (2001) [Pubmed]
  6. Mutations associated with familial melanoma impair p16INK4 function. Ranade, K., Hussussian, C.J., Sikorski, R.S., Varmus, H.E., Goldstein, A.M., Tucker, M.A., Serrano, M., Hannon, G.J., Beach, D., Dracopoli, N.C. Nat. Genet. (1995) [Pubmed]
  7. Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d. Brotherton, D.H., Dhanaraj, V., Wick, S., Brizuela, L., Domaille, P.J., Volyanik, E., Xu, X., Parisini, E., Smith, B.O., Archer, S.J., Serrano, M., Brenner, S.L., Blundell, T.L., Laue, E.D. Nature (1998) [Pubmed]
  8. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Jeffrey, P.D., Tong, L., Pavletich, N.P. Genes Dev. (2000) [Pubmed]
  9. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Guan, K.L., Jenkins, C.W., Li, Y., Nichols, M.A., Wu, X., O'Keefe, C.L., Matera, A.G., Xiong, Y. Genes Dev. (1994) [Pubmed]
  10. Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. Morse, L., Chen, D., Franklin, D., Xiong, Y., Chen-Kiang, S. Immunity (1997) [Pubmed]
  11. Indole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. Cram, E.J., Liu, B.D., Bjeldanes, L.F., Firestone, G.L. J. Biol. Chem. (2001) [Pubmed]
  12. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. Cover, C.M., Hsieh, S.J., Tran, S.H., Hallden, G., Kim, G.S., Bjeldanes, L.F., Firestone, G.L. J. Biol. Chem. (1998) [Pubmed]
  13. Crystallization of a complex between human CDK6 and a virus-encoded cyclin is critically dependent on the addition of small charged organic molecules. Schulze-Gahmen, U., Kim, S.H. Acta Crystallogr. D Biol. Crystallogr. (2001) [Pubmed]
  14. Phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1 on serine 130 is essential for viral cyclin-mediated bypass of a p21Cip1-imposed G1 arrest. Järviluoma, A., Child, E.S., Sarek, G., Sirimongkolkasem, P., Peters, G., Ojala, P.M., Mann, D.J. Mol. Cell. Biol. (2006) [Pubmed]
  15. A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. Brandi, G., Paiardini, M., Cervasi, B., Fiorucci, C., Filippone, P., De Marco, C., Zaffaroni, N., Magnani, M. Cancer Res. (2003) [Pubmed]
  16. Cyclin D-CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. Parry, D., Mahony, D., Wills, K., Lees, E. Mol. Cell. Biol. (1999) [Pubmed]
  17. Biochemical characterization of p16INK4- and p18-containing complexes in human cell lines. Ragione, F.D., Russo, G.L., Oliva, A., Mercurio, C., Mastropietro, S., Pietra, V.D., Zappia, V. J. Biol. Chem. (1996) [Pubmed]
  18. CAK-independent activation of CDK6 by a viral cyclin. Kaldis, P., Ojala, P.M., Tong, L., Mäkelä, T.P., Solomon, M.J. Mol. Biol. Cell (2001) [Pubmed]
  19. Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia. Chilosi, M., Doglioni, C., Yan, Z., Lestani, M., Menestrina, F., Sorio, C., Benedetti, A., Vinante, F., Pizzolo, G., Inghirami, G. Am. J. Pathol. (1998) [Pubmed]
  20. Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation. Franklin, D.S., Xiong, Y. Mol. Biol. Cell (1996) [Pubmed]
  21. Retinoblastoma protein-overexpressing HL60 cells resistant to 1,25-dihydroxyvitamin D3 display increased CDK2 and CDK6 activity and shortened G1 phase. Wang, Q.M., Luo, X., Kheir, A., Coffman, F.D., Studzinski, G.P. Oncogene (1998) [Pubmed]
  22. Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. Lu, H., Chang, D.J., Baratte, B., Meijer, L., Schulze-Gahmen, U. J. Med. Chem. (2005) [Pubmed]
  23. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Gao, N., Flynn, D.C., Zhang, Z., Zhong, X.S., Walker, V., Liu, K.J., Shi, X., Jiang, B.H. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  24. Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule. Fåhraeus, R., Laín, S., Ball, K.L., Lane, D.P. Oncogene (1998) [Pubmed]
  25. A p18 mutant defective in CDK6 binding in human breast cancer cells. Lapointe, J., Lachance, Y., Labrie, Y., Labrie, C. Cancer Res. (1996) [Pubmed]
  26. A pivotal role of cyclin D3 and cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-mediated human B cell proliferation. Wagner, E.F., Hleb, M., Hanna, N., Sharma, S. J. Immunol. (1998) [Pubmed]
  27. Modulation of the p27kip1 cyclin-dependent kinase inhibitor expression during IL-4-mediated human B cell activation. Blanchard, D.A., Affredou, M.T., Vazquez, A. J. Immunol. (1997) [Pubmed]
  28. The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. Godden-Kent, D., Talbot, S.J., Boshoff, C., Chang, Y., Moore, P., Weiss, R.A., Mittnacht, S. J. Virol. (1997) [Pubmed]
  29. Cyclin-mediated export of human Orc1. Laman, H., Peters, G., Jones, N. Exp. Cell Res. (2001) [Pubmed]
  30. Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Zhang, J., Hsu B A, J.C., Kinseth B A, M.A., Bjeldanes, L.F., Firestone, G.L. Cancer (2003) [Pubmed]
  31. Differential expression and regulation of Cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for Cyclin D1 function in G1 progression. Tam, S.W., Theodoras, A.M., Shay, J.W., Draetta, G.F., Pagano, M. Oncogene (1994) [Pubmed]
  32. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Alcorta, D.A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., Barrett, J.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  33. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Ely, S., Di Liberto, M., Niesvizky, R., Baughn, L.B., Cho, H.J., Hatada, E.N., Knowles, D.M., Lane, J., Chen-Kiang, S. Cancer Res. (2005) [Pubmed]
  34. Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation. Nagasawa, M., Melamed, I., Kupfer, A., Gelfand, E.W., Lucas, J.J. J. Immunol. (1997) [Pubmed]
  35. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. Mendrzyk, F., Radlwimmer, B., Joos, S., Kokocinski, F., Benner, A., Stange, D.E., Neben, K., Fiegler, H., Carter, N.P., Reifenberger, G., Korshunov, A., Lichter, P. J. Clin. Oncol. (2005) [Pubmed]
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