INHIBITION OF G1 PHASE CYCLIN-DEPENDENT KINASES BY TRANSFORMING GROWTH-FACTOR-BETA-1

Transforming growth factor beta 1 (TGF beta 1) inhibits epithelial cell proliferation late in the G1 phase of the cell cycle. We examined the effect of TGF beta 1 on known late G1 cell cycle regulators in an attempt to determine the molecular mechanism of growth inhibition by this physiological inhibitor. The results demonstrate that TGF beta 1 inhibits the late G1 and S phase specific histone H1 kinase activity of p33(cdk2). This inhibition is not due to TGF beta 1's effect on p33(cdk2) synthesis, but rather due to its negative effects on the late G1 phosphorylation of p33(cdk2). It is also shown that TGF beta 1 inhibits both late G1 cyclin A and cyclin E associated histone H1 kinase activities. The inhibitor has no effects on the synthesis of cyclin E but is shown to inhibit the synthesis of cyclin A protein in a cell cycle dependent manner. If TGF beta 1 is added to cells which have progressed further than 8 hours into G1, then it is without inhibitory effect on cyclin A synthesis. These effects of TGF beta 1 on late G1 cell cycle regulators correlate well with its inhibitory effects on cellular growth and suggest that these G1 cyclin dependent kinases might serve as targets for TGF beta 1-mediated growth arrest. (C) 1994 Wiley-Liss, Inc.