Cyclin-dependent kinase activity is regulated by T-loop phosphorylation (Thr172 in the case of CDK4), by the abundance of their cyclin partners, and by association with CDK inhibitors of the Cip/Kip or INK family of proteins . The inactive ternary complex of CDK4/cyclin D and p27 Kip1/Cip1 requires extracellular mitogenic stimuli for the release and degradation of p27, which affects progression through the restriction point and pRb-dependent entry into S-phase . The active complex of CDK4/cyclin D targets the retinoblastoma protein for phosphorylation, allowing the release of E2F transcription factors that activate G1/S-phase gene expression . In HeLa cells, upon UV irradiation, upregulation of p16 INK4A association with CDK4/cyclin D3 leads to a G2 delay, implicating CDK4/cyclin D3 activity in progression through the G2-phase of the cell cycle .
Hirai, H. et al. (1995) Mol. Cell. Biol. 15, 2672-2681.
Sherr, C.J. (1996) Science 274, 1672-1677.
Lukas, J. et al. (1996) Mol. Cell. Biol. 16, 6917-6925.
Gabrielli, B.G. et al. (1999) J Biol Chem 274, 13961-9.
