Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1)

Proliferation and apoptosis are increased in many types of inflammatory dis eases. A role for the cyclin kinase inhibitor p27(Kip1) (p27) in limiting p roliferation has been shown. In this study, we show that p27(-/-) mesangial cells and fibroblasts have strikingly elevated rates of apoptosis, not pro liferation, when deprived of growth factors. Apoptosis was rescued by resto ration of p27 expression. Cyclin A-cyclin-dependent kinase 2 (CDK2) activit y, but not cyclin E-CDK2 activity, was increased in serum-starved p27-/- ce lls, and decreasing CDK2 activity, either pharmacologically (Roscovitine) o r by a dominant-negative mutant, inhibited apoptosis, Our results show that a new biological function for the CDK inhibitor p27 is protection of cells from apoptosis by constraining CDK2 activity. These results suggest that C DK inhibitors are necessary for coordinating the cell cycle and cell-death programs so that cell viability is maintained during exit from the cell cyc le.