G(1) CONTROL IN MAMMALIAN-CELLS

Cyclin-dependent kinases (Cdks) control the major cell cycle transitio ns in eukaryotic cells. On the basis of a variety of experiments where cyclin function either is impaired or enhanced, D-type cyclins as wel l as cyclins E and A have been linked to G(1) and G(1)/S phase roles i n mammalian cells. We therefore sought to determine if agents that blo ck the G(1)/S phase transition do so at the level of regulating the Cd k activities associated with these cyclins. A variety of conditions th at lead to G(1) arrest were found to correlate with accumulation of G( 1)-specific Cdk inhibitors, including treatment of fibroblasts with io nizing radiation, treatment of epithelial cells with TGF-beta, treatme nt of HeLa cells with the drug lovastatin, and removal of essential gr owth factors from a variety of different cell types. Mechanistically, inhibition of Cdks was found to involve the stoichiometric binding of Cdk inhibitor proteins. p21(Waf/Cip1) was associated with DNA damage i nduced arrest while p27(Kip1/)p28(Ick1) accumulated under a variety of antiproliferative conditions.