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Gene Review

Cdk4  -  cyclin-dependent kinase 4

Mus musculus

Synonyms: CRK3, Cell division protein kinase 4, Crk3, Cyclin-dependent kinase 4, PSK-J3, ...
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Disease relevance of Cdk4

  • Cell cycle effects of CINK4 on tumor and normal cells were studied by flow cytometry, and changes in phosphorylation of the retinoblastoma protein (pRb), a substrate of Cdk4, were determined by western blotting [1].
  • Mice lacking the Cdk4 gene exhibit various defects in many organs associated with hypocellularity, whereas loss of the p18(Ink4c) gene results in widespread hyperplasia and organomegaly [2].
  • Our results indicate that overexpression of cyclin D1 and Cdk4 occurs in intestinal adenomas and is associated with increased cell proliferative activity in premalignant neoplastic cells [3].
  • These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability [4].
  • Although Cdk4-null mice show no embryonic lethality, they exhibit specific endocrine phenotypes, i.e. dwarfism, infertility, and diabetes [5].

High impact information on Cdk4


Chemical compound and disease context of Cdk4


Biological context of Cdk4

  • We sought to identify a small molecule that could inhibit the kinase activity of Cdk4 in vitro and to then ascertain the effects of that inhibitor on cell growth and tumor volume in vivo [1].
  • The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2 [12].
  • The double-mutant mice exhibited phenotypes very close to or indistinguishable from that of Cdk4 single-mutant mice [2].
  • To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4-/- mice [4].
  • Cdk4 siRNA also inhibits estrogen-dependent cell proliferation in GH3 cells and closely related GH4 cells [5].

Anatomical context of Cdk4

  • Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D-Cdk4 function in the mammary gland [13].
  • Cdk4 nuclear immunoreactivity was restricted to the crypt areas in morphologically normal small intestine and colon [3].
  • Furthermore, Cdk4 siRNA does not affect GHRH-induced proliferation of mouse embryonic fibroblasts or estrogen-dependent proliferation of mammary carcinoma MCF-7 cells [5].
  • Cyclin D-dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines [14].
  • C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G(1) cell cycle phase [14].

Associations of Cdk4 with chemical compounds

  • Cells transformed with Cdk4 expression vectors, with or without cyclin D3 expression vectors, also undergo G0 arrest in the presence of dexamethasone [15].
  • Mutation of serine 795 to alanine prevents pRb inactivation by Cdk4 phosphorylation in the microinjection assay [16].
  • Taken together, our results indicate that the overall defects in growth, fertility and pancreatic development in Cdk4-deficient mice may be a combination of cell-type specific defects and altered glucose metabolism, as a result of defects in postnatal pancreatic development [17].
  • Pharmacological treatment of SOD1(G37R) mice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb [18].
  • Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation [19].

Physical interactions of Cdk4

  • These observations show that specificity exists between Cdk4/6-cyclin D complexes and their ability to be targeted by p16 [20].
  • These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization [21].
  • This CDK4 activity was due to complexes of cyclin D2/CDK4 [22].
  • Using a mouse macrophage cell line (Bac1.2F5), we found that most of Cdk4 bound to p15 when cells were in a quiescent state [23].

Regulatory relationships of Cdk4


Other interactions of Cdk4

  • Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4 [29].
  • These results indicate that glucocorticoid inhibition of fibroblast proliferation is due to induction of p21Cip1, which binds to and inactivates cyclinD/Cdk4 complexes [30].
  • Both promoters are repressed by p16INK4 and this repression can be released by overexpression of cdk4 [31].
  • The pRb kinase activity of cyclin D3 and CDK4 was not detected in quiescent 3T3-L1 cells and was then induced as the cells entered the mitotic clonal expansion phase [32].
  • The level of p27KiP1 and p27-CDK4 complexes remain high during differentiation and in mature adipocytes [32].

Analytical, diagnostic and therapeutic context of Cdk4

  • For both cyclin D1 and Cdk4, protein and mRNA levels were increased in intestinal adenomas but not in normal intestinal epithelium as determined by immunohistochemistry, in situ hybridization, and reverse transcription-PCR [33].
  • Individual antibodies of our panel recognize distinct pools of Cdk4/6, a feature reflected by their differential applicability in immunoblotting, immunoprecipitation, kinase assays, and immunostaining including immunohistochemistry on archival paraffin-embedded tissue sections [34].
  • Localization of the target epitopes was mapped by peptide enzyme-linked immunoadsorbent assay (ELISA), and two antibodies recognizing sequences adjacent to N-terminus of Cdk4 can discriminate between the wild-type protein and the oncogenic, melanoma-associated R24C mutant of this kinase [34].
  • Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts [35].
  • Cdk4 null mice display also reduced body and organ size [36].


  1. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. Soni, R., O'Reilly, T., Furet, P., Muller, L., Stephan, C., Zumstein-Mecker, S., Fretz, H., Fabbro, D., Chaudhuri, B. J. Natl. Cancer Inst. (2001) [Pubmed]
  2. Genetic evidence for functional dependency of p18Ink4c on Cdk4. Pei, X.H., Bai, F., Tsutsui, T., Kiyokawa, H., Xiong, Y. Mol. Cell. Biol. (2004) [Pubmed]
  3. Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Zhang, T., Nanney, L.B., Luongo, C., Lamps, L., Heppner, K.J., DuBois, R.N., Beauchamp, R.D. Cancer Res. (1997) [Pubmed]
  4. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Reddy, H.K., Mettus, R.V., Rane, S.G., Graña, X., Litvin, J., Reddy, E.P. Cancer Res. (2005) [Pubmed]
  5. Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. Jirawatnotai, S., Aziyu, A., Osmundson, E.C., Moons, D.S., Zou, X., Kineman, R.D., Kiyokawa, H. J. Biol. Chem. (2004) [Pubmed]
  6. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Malumbres, M., Sotillo, R., Santamaría, D., Galán, J., Cerezo, A., Ortega, S., Dubus, P., Barbacid, M. Cell (2004) [Pubmed]
  7. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Rane, S.G., Dubus, P., Mettus, R.V., Galbreath, E.J., Boden, G., Reddy, E.P., Barbacid, M. Nat. Genet. (1999) [Pubmed]
  8. Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo. Huang, Z.Y., Baldwin, R.L., Hedrick, N.M., Gutmann, D.H. Oncogene (2002) [Pubmed]
  9. Activating point mutations in cyclin-dependent kinase 4 are not seen in sporadic pituitary adenomas, insulinomas or Leydig cell tumours. Vax, V.V., Bibi, R., Diaz-Cano, S., Gueorguiev, M., Kola, B., Borboli, N., Bressac-de Paillerets, B., Walker, G.J., Dedov, I.I., Grossman, A.B., Korbonits, M. J. Endocrinol. (2003) [Pubmed]
  10. Human melanocyte senescence and melanoma susceptibility genes. Bennett, D.C. Oncogene (2003) [Pubmed]
  11. Deregulation of the cyclin D1/Cdk4 retinoblastoma pathway in rat mammary gland carcinomas induced by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Qiu, C., Shan, L., Yu, M., Snyderwine, E.G. Cancer Res. (2003) [Pubmed]
  12. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Kitagawa, M., Higashi, H., Jung, H.K., Suzuki-Takahashi, I., Ikeda, M., Tamai, K., Kato, J., Segawa, K., Yoshida, E., Nishimura, S., Taya, Y. EMBO J. (1996) [Pubmed]
  13. Cyclin-dependent kinase inhibitor p27(Kip1) is required for mouse mammary gland morphogenesis and function. Muraoka, R.S., Lenferink, A.E., Simpson, J., Brantley, D.M., Roebuck, L.R., Yakes, F.M., Arteaga, C.L. J. Cell Biol. (2001) [Pubmed]
  14. Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. Saab, R., Bills, J.L., Miceli, A.P., Anderson, C.M., Khoury, J.D., Fry, D.W., Navid, F., Houghton, P.J., Skapek, S.X. Mol. Cancer Ther. (2006) [Pubmed]
  15. c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. Rhee, K., Bresnahan, W., Hirai, A., Hirai, M., Thompson, E.A. Cancer Res. (1995) [Pubmed]
  16. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Connell-Crowley, L., Harper, J.W., Goodrich, D.W. Mol. Biol. Cell (1997) [Pubmed]
  17. Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Mettus, R.V., Rane, S.G. Oncogene (2003) [Pubmed]
  18. Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. Nguyen, M.D., Boudreau, M., Kriz, J., Couillard-Després, S., Kaplan, D.R., Julien, J.P. J. Neurosci. (2003) [Pubmed]
  19. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Kato, J.Y., Matsuoka, M., Polyak, K., Massagué, J., Sherr, C.J. Cell (1994) [Pubmed]
  20. Cdk6-cyclin D3 activity in murine ES cells is resistant to inhibition by p16(INK4a). Faast, R., White, J., Cartwright, P., Crocker, L., Sarcevic, B., Dalton, S. Oncogene (2004) [Pubmed]
  21. A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase. Diehl, J.A., Sherr, C.J. Mol. Cell. Biol. (1997) [Pubmed]
  22. Cyclin D2 compensates for the loss of cyclin D1 in estrogen-induced mouse uterine epithelial cell proliferation. Chen, B., Pollard, J.W. Mol. Endocrinol. (2003) [Pubmed]
  23. Cdk4 activation is dependent on the subunit rearrangement in the complexes. Takahashi, H., Menjo, M., Kaneko, Y., Ikeda, K., Matsushime, H., Nakanishi, M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  24. Inhibition of retinoblastoma protein phosphorylation by myogenesis-induced changes in the subunit composition of the cyclin-dependent kinase 4 complex. Wang, J., Walsh, K. Cell Growth Differ. (1996) [Pubmed]
  25. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Tsutsui, T., Hesabi, B., Moons, D.S., Pandolfi, P.P., Hansel, K.S., Koff, A., Kiyokawa, H. Mol. Cell. Biol. (1999) [Pubmed]
  26. Inhibition of Cdk4 activity enhances translation of p27kip1 in quiescent Rb-negative cells. González, T., Seoane, M., Caamaño, P., Viñuela, J., Domínguez, F., Zalvide, J. J. Biol. Chem. (2003) [Pubmed]
  27. High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27(Kip) Cdk-complexes. Groth, A., Willumsen, B.M. Cell. Signal. (2005) [Pubmed]
  28. Cyclin D1-cdk4 induce runx2 ubiquitination and degradation. Shen, R., Wang, X., Drissi, H., Liu, F., O'Keefe, R.J., Chen, D. J. Biol. Chem. (2006) [Pubmed]
  29. D-type cyclin-dependent kinase activity in mammalian cells. Matsushime, H., Quelle, D.E., Shurtleff, S.A., Shibuya, M., Sherr, C.J., Kato, J.Y. Mol. Cell. Biol. (1994) [Pubmed]
  30. Glucocorticoid inhibition of fibroblast proliferation and regulation of the cyclin kinase inhibitor p21Cip1. Ramalingam, A., Hirai, A., Thompson, E.A. Mol. Endocrinol. (1997) [Pubmed]
  31. Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Schulze, A., Zerfass, K., Spitkovsky, D., Henglein, B., Jansen-Dürr, P. Oncogene (1994) [Pubmed]
  32. Regulation of cyclin-dependent kinase 4 during adipogenesis involves switching of cyclin D subunits and concurrent binding of p18INK4c and p27Kip1. Phelps, D.E., Xiong, Y. Cell Growth Differ. (1998) [Pubmed]
  33. Decreased transforming growth factor beta type II receptor expression in intestinal adenomas from Min/+ mice is associated with increased cyclin D1 and cyclin-dependent kinase 4 expression. Zhang, T., Nanney, L.B., Peeler, M.O., Williams, C.S., Lamps, L., Heppner, K.J., DuBois, R.N., Beauchamp, R.D. Cancer Res. (1997) [Pubmed]
  34. Immunohistochemical analysis of the D-type cyclin-dependent kinases Cdk4 and Cdk6, using a series of monoclonal antibodies. Lukas, C., Jensen, S.K., Bartkova, J., Lukas, J., Bartek, J. Hybridoma (1999) [Pubmed]
  35. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Fry, D.W., Harvey, P.J., Keller, P.R., Elliott, W.L., Meade, M., Trachet, E., Albassam, M., Zheng, X., Leopold, W.R., Pryer, N.K., Toogood, P.L. Mol. Cancer Ther. (2004) [Pubmed]
  36. Genetic rescue of Cdk4 null mice restores pancreatic beta-cell proliferation but not homeostatic cell number. Martín, J., Hunt, S.L., Dubus, P., Sotillo, R., Néhmé-Pélluard, F., Magnuson, M.A., Parlow, A.F., Malumbres, M., Ortega, S., Barbacid, M. Oncogene (2003) [Pubmed]
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