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 epithelial cell growth. Cyclins E and A in association with Cdk2 have been 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 by 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 the activation of cyclin E-associated kinase that normally accompanies the G(1)-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G(0)-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.