Regulation by transforming growth factor-beta 1 of G1 cyclin-dependent kinases in human retinal epithelial cells

Transforming growth factor beta (TGF beta) is a potent inhibitor of epithel ial cell proliferation, delaying or arresting cell cycle progression in mid -late G1, in long-term life span cells this growth inhibitory action has be en attributed to regulatory events on bork the levels and activities of G1 cyclin-dependent kinases (CDKs). CDK inhibitors have been shown to play imp ortant role in the TGF beta-induced inhibition of G1 CDKs. In this work, we have investigated the effect of TGF beta 1 on both cell proliferation and G1 CDK activities in primary cultures of human retinal pigment epithelial ( RPE) cells. We show that TCF beta 1 exerts a partial inhibitory effect on R PE cell proliferation by causing a significant increase of the RPE cell num ber in G1. TGF beta 1 induces an up-regulation of the CDK inhibitor p15(INK 4B) with its subsequent association to CDK4, and a decline in CDK4 protein level. In parallel, rye have observed a decline of p27(KIP1) associated to CDK4 and a significant increase of the inhibitor associated to CDK2. Finall y, we shown that TGF beta 1 reduces both CDK4 and CDK2 enzymatic activities . The Fact that TCF beta exerts only partial inhibitions on G1 CDKs and cel l cycle progression in RPE cells suggests a propensity of these cells to es cape from the anti-proliferative action of the cytokine, a phenomenon which could be reinforced during the development of proliferative vitreoretinopa thy. (C) 1999 Academic Press.