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Gene Review

CDK4  -  cyclin-dependent kinase 4

Homo sapiens

Synonyms: CMM3, Cell division protein kinase 4, Cyclin-dependent kinase 4, PSK-J3
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Disease relevance of CDK4

  • CDK4 associates separately with a protein of M(r) 16K, particularly in cells lacking a functional retinoblastoma protein [1].
  • CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma [2].
  • The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patient's lymphocytes [3].
  • CONCLUSIONS: Aberrant expression of cyclins D1, D2, CDK4, p16, and pRB occur in significant subsets of exophytic and flat adenomas, particularly among cases with high-grade dysplasia [4].
  • Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types [5].

Psychiatry related information on CDK4


High impact information on CDK4

  • Tax exerts (a) trans-activation and -repression of transcription of different sets of cellular genes through binding to groups of transcription factors and coactivators, (b) dysregulation of cell cycle through binding to inhibitors of CDK4/6, and (c) inhibition of some tumor suppressor proteins [7].
  • These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers [8].
  • Degradation is mediated through a previously unrecognized destruction box in cyclin D1 and leads to a release of p21cip1 from CDK4 to inhibit CDK2 [9].
  • We present evidence that phosphorylation of the C-terminal region of Rb by Cdk4/6 initiates successive intramolecular interactions between the C-terminal region and the central pocket [10].
  • Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma [11].

Chemical compound and disease context of CDK4


Biological context of CDK4


Anatomical context of CDK4


Associations of CDK4 with chemical compounds

  • Surprisingly, CDK4 immunoprecipitates derived from Flavopiridol-treated MCF-7 cells (3 h, 300 nM Flavonolpiridol) had an approximately 3-fold increased kinase activity compared with untreated cells [22].
  • We found that expression of CDK2 and CDK4 genes were up-regulated within hours of androgen treatment as detected in Northern and Western blot analyses [12].
  • Others have shown that a specific mutation in the NH2-terminal region of the CDK4 gene product can disrupt p16INK4a binding, thereby bypassing its inhibitory activity [23].
  • The phosphatidylinositol 3-OH-kinase inhibitor LY294002 has been shown to block cyclin D1 accumulation, CDK4 activity and, thus, G1 progression in alpha-thrombin-stimulated IIC9 cells (Chinese hamster embryonic fibroblasts) [24].
  • Our results show that a herbimycin A- and staurosporine-sensitive phase of CDK4 expression and activity preceded the acquisition of IL-2-responsiveness in mitogen-stimulated peripheral blood T cells [25].

Physical interactions of CDK4


Enzymatic interactions of CDK4

  • CDK2 and CDK4 known promoter of cell cycling catalyze phosphorylation of RB protein [31].
  • Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb [32].
  • Here, we report that CDK4 complexes from Nalm-6 extracts phosphorylated in vitro the CDK2-preferred serine 612, which was inhibited by p16INK4a, and fascaplysin [33].
  • A conserved site at Ser842 in the related pocket protein p107 is also preferentially phosphorylated by cdk4/D1 [34].

Regulatory relationships of CDK4


Other interactions of CDK4

  • 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) [40].
  • Addition of p34(SEI-1) to cyclin D1-CDK4 renders the complex resistant to inhibition by p16(INK4a) [41].
  • Consistent with this result, kinase activity of CDK2 was significantly down-regulated in cells overexpressing APC although its synthesis remained unchanged, while CDK4 activity was barely affected [42].
  • In contrast, neither CDK4 nor CDK7 itself can phosphorylate the CDK7 T loop in vitro [43].
  • Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes [44].

Analytical, diagnostic and therapeutic context of CDK4


  1. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Serrano, M., Hannon, G.J., Beach, D. Nature (1993) [Pubmed]
  2. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Lazarov, M., Kubo, Y., Cai, T., Dajee, M., Tarutani, M., Lin, Q., Fang, M., Tao, S., Green, C.L., Khavari, P.A. Nat. Med. (2002) [Pubmed]
  3. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Wölfel, T., Hauer, M., Schneider, J., Serrano, M., Wölfel, C., Klehmann-Hieb, E., De Plaen, E., Hankeln, T., Meyer zum Büschenfelde, K.H., Beach, D. Science (1995) [Pubmed]
  4. Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon. Bartkova, J., Thullberg, M., Slezak, P., Jaramillo, E., Rubio, C., Thomassen, L.H., Bartek, J. Gastroenterology (2001) [Pubmed]
  5. Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Korz, C., Pscherer, A., Benner, A., Mertens, D., Schaffner, C., Leupolt, E., Döhner, H., Stilgenbauer, S., Lichter, P. Blood (2002) [Pubmed]
  6. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. McShea, A., Harris, P.L., Webster, K.R., Wahl, A.F., Smith, M.A. Am. J. Pathol. (1997) [Pubmed]
  7. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Yoshida, M. Annu. Rev. Immunol. (2001) [Pubmed]
  8. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Narita, M., Narita, M., Krizhanovsky, V., Nuñez, S., Chicas, A., Hearn, S.A., Myers, M.P., Lowe, S.W. Cell (2006) [Pubmed]
  9. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Agami, R., Bernards, R. Cell (2000) [Pubmed]
  10. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Harbour, J.W., Luo, R.X., Dei Santi, A., Postigo, A.A., Dean, D.C. Cell (1999) [Pubmed]
  11. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Zuo, L., Weger, J., Yang, Q., Goldstein, A.M., Tucker, M.A., Walker, G.J., Hayward, N., Dracopoli, N.C. Nat. Genet. (1996) [Pubmed]
  12. Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes. Lu, S., Tsai, S.Y., Tsai, M.J. Cancer Res. (1997) [Pubmed]
  13. Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. Tsao, H., Benoit, E., Sober, A.J., Thiele, C., Haluska, F.G. Cancer Res. (1998) [Pubmed]
  14. Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. Flores, J.F., Pollock, P.M., Walker, G.J., Glendening, J.M., Lin, A.H., Palmer, J.M., Walters, M.K., Hayward, N.K., Fountain, J.W. Oncogene (1997) [Pubmed]
  15. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Mukhopadhyay, A., Banerjee, S., Stafford, L.J., Xia, C., Liu, M., Aggarwal, B.B. Oncogene (2002) [Pubmed]
  16. Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). Chen, W.J., Chang, C.Y., Lin, J.K. Biochem. Pharmacol. (2003) [Pubmed]
  17. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Kato, J., Matsushime, H., Hiebert, S.W., Ewen, M.E., Sherr, C.J. Genes Dev. (1993) [Pubmed]
  18. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M., Måsbäck, A., Westerdahl, J., Olsson, H., Ingvar, C. J. Natl. Cancer Inst. (2000) [Pubmed]
  19. Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Haller, K., Wu, Y., Derow, E., Schmitt, I., Jeang, K.T., Grassmann, R. Mol. Cell. Biol. (2002) [Pubmed]
  20. Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors". Bockstaele, L., Kooken, H., Libert, F., Paternot, S., Dumont, J.E., de Launoit, Y., Roger, P.P., Coulonval, K. Mol. Cell. Biol. (2006) [Pubmed]
  21. Deregulation of the RB pathway in human testicular germ cell tumours. Bartkova, J., Lukas, C., Sørensen, C.S., Meyts, E.R., Skakkebaek, N.E., Lukas, J., Bartek, J. J. Pathol. (2003) [Pubmed]
  22. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Carlson, B.A., Dubay, M.M., Sausville, E.A., Brizuela, L., Worland, P.J. Cancer Res. (1996) [Pubmed]
  23. 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]
  24. Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. Keenan, S.M., Lents, N.H., Baldassare, J.J. J. Biol. Chem. (2004) [Pubmed]
  25. CDK4 expression and activity are required for cytokine responsiveness in T cells. Modiano, J.F., Mayor, J., Ball, C., Fuentes, M.K., Linthicum, D.S. J. Immunol. (2000) [Pubmed]
  26. 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]
  27. Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4. Leng, X., Noble, M., Adams, P.D., Qin, J., Harper, J.W. Mol. Cell. Biol. (2002) [Pubmed]
  28. Identification of CDK4 sequences involved in cyclin D1 and p16 binding. Coleman, K.G., Wautlet, B.S., Morrissey, D., Mulheron, J., Sedman, S.A., Brinkley, P., Price, S., Webster, K.R. J. Biol. Chem. (1997) [Pubmed]
  29. Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells. Bindels, E.M., Lallemand, F., Balkenende, A., Verwoerd, D., Michalides, R. Oncogene (2002) [Pubmed]
  30. Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site. Li, J.M., Nichols, M.A., Chandrasekharan, S., Xiong, Y., Wang, X.F. J. Biol. Chem. (1995) [Pubmed]
  31. Biochemical characterizations reveal different properties between CDK4/cyclin D1 and CDK2/cyclin A. Kim, D.M., Yang, K., Yang, B.S. Exp. Mol. Med. (2003) [Pubmed]
  32. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Schmidt, M., Fernandez de Mattos, S., van der Horst, A., Klompmaker, R., Kops, G.J., Lam, E.W., Burgering, B.M., Medema, R.H. Mol. Cell. Biol. (2002) [Pubmed]
  33. Limited redundancy in phosphorylation of retinoblastoma tumor suppressor protein by cyclin-dependent kinases in acute lymphoblastic leukemia. Schmitz, N.M., Hirt, A., Aebi, M., Leibundgut, K. Am. J. Pathol. (2006) [Pubmed]
  34. Defining the substrate specificity of cdk4 kinase-cyclin D1 complex. Grafstrom, R.H., Pan, W., Hoess, R.H. Carcinogenesis (1999) [Pubmed]
  35. Detection of p16 gene deletions in gliomas: a comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR. Perry, A., Nobori, T., Ru, N., Anderl, K., Borell, T.J., Mohapatra, G., Feuerstein, B.G., Jenkins, R.B., Carson, D.A. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  36. Transforming growth factor B1 stimulated DNA synthesis in the granulosa cells of preantral follicles: negative interaction with epidermal growth factor. Yang, P., Roy, S.K. Biol. Reprod. (2006) [Pubmed]
  37. Evidence for a cancer-specific switch at the CDK4 promoter with loss of control by both USF and c-Myc. Pawar, S.A., Szentirmay, M.N., Hermeking, H., Sawadogo, M. Oncogene (2004) [Pubmed]
  38. Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. Ramirez, R.D., Herbert, B.S., Vaughan, M.B., Zou, Y., Gandia, K., Morales, C.P., Wright, W.E., Shay, J.W. Oncogene (2003) [Pubmed]
  39. Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits. Nielsen, E.M., Hansen, L., Stissing, T., Yanagisawa, K., Borch-Johnsen, K., Poulsen, P., Vaag, A., Hansen, T., Pedersen, O. J. Mol. Med. (2005) [Pubmed]
  40. 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]
  41. Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1). Sugimoto, M., Nakamura, T., Ohtani, N., Hampson, L., Hampson, I.N., Shimamoto, A., Furuichi, Y., Okumura, K., Niwa, S., Taya, Y., Hara, E. Genes Dev. (1999) [Pubmed]
  42. The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. Baeg, G.H., Matsumine, A., Kuroda, T., Bhattacharjee, R.N., Miyashiro, I., Toyoshima, K., Akiyama, T. EMBO J. (1995) [Pubmed]
  43. Reciprocal activation by cyclin-dependent kinases 2 and 7 is directed by substrate specificity determinants outside the T loop. Garrett, S., Barton, W.A., Knights, R., Jin, P., Morgan, D.O., Fisher, R.P. Mol. Cell. Biol. (2001) [Pubmed]
  44. CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus. Hernández, L., Beà, S., Pinyol, M., Ott, G., Katzenberger, T., Rosenwald, A., Bosch, F., López-Guillermo, A., Delabie, J., Colomer, D., Montserrat, E., Campo, E. Cancer Res. (2005) [Pubmed]
  45. Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. Dei Tos, A.P., Doglioni, C., Piccinin, S., Sciot, R., Furlanetto, A., Boiocchi, M., Dal Cin, P., Maestro, R., Fletcher, C.D., Tallini, G. J. Pathol. (2000) [Pubmed]
  46. An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cyclin-dependent kinase 4. Li, J., Joo, S.H., Tsai, M.D. Biochemistry (2003) [Pubmed]
  47. Dissection of CDK4-binding and transactivation activities of p34(SEI-1) and comparison between functions of p34(SEI-1) and p16(INK4A). Li, J., Muscarella, P., Joo, S.H., Knobloch, T.J., Melvin, W.S., Weghorst, C.M., Tsai, M.D. Biochemistry (2005) [Pubmed]
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