G1 control in mammalian cells.
Cyclin-dependent kinases (Cdks) control the major cell cycle transitions in eukaryotic cells. On the basis of a variety of experiments where cyclin function either is impaired or enhanced, D-type cyclins as well as cyclins E and A have been linked to G1 and G1/S phase roles in mammalian cells. We therefore sought to determine if agents that block the G1/S phase transition do so at the level of regulating the Cdk activities associated with these cyclins. A variety of conditions that lead to G1 arrest were found to correlate with accumulation of G1-specific Cdk inhibitors, including treatment of fibroblasts with ionizing radiation, treatment of epithelial cells with TGF-beta, treatment of HeLa cells with the drug lovastatin, and removal of essential growth factors from a variety of different cell types. Mechanistically, inhibition of Cdks was found to involve the stoichiometric binding of Cdk inhibitor proteins. p21Waf1/Cip1 was associated with DNA damage induced arrest while p27Kip1/p28Ick1 accumulated under a variety of antiproliferative conditions.
Reed
S I
SI
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.
Bailly
E
E
Dulic
V
V
Hengst
L
L
Resnitzky
D
D
Slingerland
J
J
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016213:Cyclins / Q000502:physiology*; D016193:G1 Phase; D006801:Humans
D016213:Cyclins; D018844:Cyclin-Dependent Kinases