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Gene Review

Cdk4  -  cyclin-dependent kinase 4

Rattus norvegicus

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

  • To test this hypothesis, we used the RNA alphavirus Sindbis to express three known cyclin dependent kinase inhibitors (CKIs), p16(ink4), p21(waf/cip), and p27(kip1), and dominant negative mutant forms of four known G1 cyclin dependent kinases (CDKs), Cdk2, Cdk3, Cdk4, and Cdk6, in primary cultured rat superior cervical ganglion sympathetic neurons [1].
  • Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers [2].
  • Inhibition of Cdk4 activity during this ischemia/reperfusion is highly neuroprotective [3].
  • Coinfection of recombinant adenoviruses expressing D1NLS and CDK4 induced Rb phosphorylation and CDK2 kinase activity [4].

High impact information on Cdk4


Biological context of Cdk4


Anatomical context of Cdk4


Associations of Cdk4 with chemical compounds


Regulatory relationships of Cdk4


Other interactions of Cdk4

  • ATRA did not influence the expressions of Cip/Kip family Cdk inhibitors or those of cyclins D1 and D2, whereas it strongly inhibited the expressions of cyclins D3 and E, Cdk4, Cdk6, and Cdk2 [20].
  • In addition, we show that expression of dominant negative forms of Cdk4 or Cdk6, but not Cdk2 or Cdk3, protects NGF-deprived sympathetic neurons from death [1].
  • The levels of cyclin D1 increased 5.8-fold and Cdk4 increased by 4.4-fold by 24 hours after reseeding the day 9 density-arrested cultures, coincident with the increase in DNA synthesis [9].
  • Recovery of Cdk4-dependent kinase activity occurred by 4 hours after release from growth arrest, coincident with decreased binding of p21 to the complex [9].
  • Cdk-activating kinase did not rescue Cdk4/6 activity [8].

Analytical, diagnostic and therapeutic context of Cdk4


  1. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. Park, D.S., Levine, B., Ferrari, G., Greene, L.A. J. Neurosci. (1997) [Pubmed]
  2. Expression of G1 phase-related cell cycle molecules in naturally developing hepatocellular carcinoma of Long-Evans Cinnamon rats. Kita, Y., Masaki, T., Funakoshi, F., Yoshida, S., Tanaka, M., Kurokohchi, K., Uchida, N., Watanabe, S., Matsumoto, K., Kuriyama, S. Int. J. Oncol. (2004) [Pubmed]
  3. Cell-cycle regulators are involved in transient cerebral ischemia induced neuronal apoptosis in female rats. Wen, Y., Yang, S., Liu, R., Simpkins, J.W. FEBS Lett. (2005) [Pubmed]
  4. Critical role of cyclin D1 nuclear import in cardiomyocyte proliferation. Tamamori-Adachi, M., Ito, H., Sumrejkanchanakij, P., Adachi, S., Hiroe, M., Shimizu, M., Kawauchi, J., Sunamori, M., Marumo, F., Kitajima, S., Ikeda, M.A. Circ. Res. (2003) [Pubmed]
  5. Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Terada, Y., Tatsuka, M., Jinno, S., Okayama, H. Nature (1995) [Pubmed]
  6. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Serrano, M., Gómez-Lahoz, E., DePinho, R.A., Beach, D., Bar-Sagi, D. Science (1995) [Pubmed]
  7. Oncogenic stimulation recruits cyclin-dependent kinase in the cell cycle start in rat fibroblast. Jinno, S., Hung, S.C., Yamamoto, H., Lin, J., Nagata, A., Okayama, H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  8. The proto-oncogene c-myc acts through the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) to facilitate the activation of Cdk4/6 and early G(1) phase progression. Obaya, A.J., Kotenko, I., Cole, M.D., Sedivy, J.M. J. Biol. Chem. (2002) [Pubmed]
  9. Intestinal cell cycle regulations. Interactions of cyclin D1, Cdk4, and p21Cip1. Beauchamp, R.D., Sheng, H.M., Shao, J.Y., Thompson, E.A., Ko, T.C. Ann. Surg. (1996) [Pubmed]
  10. Cyclin-dependent kinases as a therapeutic target for stroke. Osuga, H., Osuga, S., Wang, F., Fetni, R., Hogan, M.J., Slack, R.S., Hakim, A.M., Ikeda, J.E., Park, D.S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  11. Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells. Ko, T.C., Sheng, H.M., Reisman, D., Thompson, E.A., Beauchamp, R.D. Oncogene (1995) [Pubmed]
  12. Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts. Fujita, M., Urano, T., Horie, K., Ikeda, K., Tsukui, T., Fukuoka, H., Tsutsumi, O., Ouchi, Y., Inoue, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  13. Inactivation of the cyclin D-dependent kinase in the rat fibroblast cell line, 3Y1, induced by contact inhibition. Kato, A., Takahashi, H., Takahashi, Y., Matsushime, H. J. Biol. Chem. (1997) [Pubmed]
  14. Calmodulin binds to p21(Cip1) and is involved in the regulation of its nuclear localization. Taulés, M., Rodríguez-Vilarrupla, A., Rius, E., Estanyol, J.M., Casanovas, O., Sacks, D.B., Pérez-Payá, E., Bachs, O., Agell, N. J. Biol. Chem. (1999) [Pubmed]
  15. Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression. Gingras, B., Rodier, G., Giasson, E., Coulombe, P., Chassagne, C., Meloche, S. Oncogene (2003) [Pubmed]
  16. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. Toogood, P.L., Harvey, P.J., Repine, J.T., Sheehan, D.J., VanderWel, S.N., Zhou, H., Keller, P.R., McNamara, D.J., Sherry, D., Zhu, T., Brodfuehrer, J., Choi, C., Barvian, M.R., Fry, D.W. J. Med. Chem. (2005) [Pubmed]
  17. Association of cyclin-dependent kinase-4 and cyclin D1 in neonatal beta cells after mitogenic stimulation by lysophosphatidic acid. Dunlop, M., Muggli, E., Clark, S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  18. Cyclin-dependent kinase 4 and cyclin D1 are required for excitotoxin-induced neuronal cell death in vivo. Ino, H., Chiba, T. J. Neurosci. (2001) [Pubmed]
  19. Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells. Terada, Y., Inoshita, S., Nakashima, O., Yamada, T., Tamamori, M., Ito, H., Sasaki, S., Marumo, F. Kidney Int. (1998) [Pubmed]
  20. All-trans retinoic acid inhibits vascular smooth muscle cell proliferation targeting multiple genes for cyclins and cyclin-dependent kinases. Kosaka, C., Sasaguri, T., Komiyama, Y., Takahashi, H. Hypertens. Res. (2001) [Pubmed]
  21. Regulation of G(1) cyclin-dependent kinases in the liver: role of nuclear localization and p27 sequestration. Albrecht, J.H., Rieland, B.M., Nelsen, C.J., Ahonen, C.L. Am. J. Physiol. (1999) [Pubmed]
  22. Early deregulation of the the p16ink4a-cyclin D1/cyclin-dependent kinase 4-retinoblastoma pathway in cell proliferation-driven esophageal tumorigenesis in zinc-deficient rats. Fong, L.Y., Nguyen, V.T., Farber, J.L., Huebner, K., Magee, P.N. Cancer Res. (2000) [Pubmed]
  23. Overexpression of cell cycle inhibitors (p16INK4 and p21Cip1) and cyclin D1 using adenovirus vectors regulates proliferation of rat mesangial cells. Terada, Y., Yamada, T., Nakashima, O., Tamamori, M., Ito, H., Sasaki, S., Marumo, F. J. Am. Soc. Nephrol. (1997) [Pubmed]
  24. Expression of cyclins D1, D2 and E correlates with proliferation of rat stellate cells in culture. Kawada, N., Ikeda, K., Seki, S., Kuroki, T. J. Hepatol. (1999) [Pubmed]
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