A NOVEL INHIBITOR OF CYCLIN-CDK ACTIVITY DETECTED IN TRANSFORMING GROWTH-FACTOR BETA-ARRESTED EPITHELIAL-CELLS

Transforming growth factor beta (TGF-beta) is a potent inhibitor of ep ithelial cell growth. Cyclins E and A in association with Cdk2 have be en shown to play a role in the G(1)-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G(1)/S cyclins E and A. Inhibition of cyclin A-associated kinase b y TGP-beta is primarily due to a decrease in cyclin A mRNA and protein . By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that th e activation of cyclin E-associated kinase that normally accompanies t he G(1)-to-S phase transition is inhibited. A novel inhibitor of cycli n-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibit ion is mediated by a heat-stable protein that targets both Cdk2 and Cd c2 kinases. In G(0)-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyc lin-dependent kinases induced under different conditions to mediate an tiproliferative responses.