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

Transforming growth factor beta 1 (TGF beta 1) inhibits epithelial cel l proliferation late in the G1 phase of the cell cycle. We examined th e effect of TGF beta 1 on known late G1 cell cycle regulators in an at tempt to determine the molecular mechanism of growth inhibition by thi s physiological inhibitor. The results demonstrate that TGF beta 1 inh ibits the late G1 and S phase specific histone H1 kinase activity of p 33(cdk2). This inhibition is not due to TGF beta 1's effect on p33(cdk 2) synthesis, but rather due to its negative effects on the late G1 ph osphorylation of p33(cdk2). It is also shown that TGF beta 1 inhibits both late G1 cyclin A and cyclin E associated histone H1 kinase activi ties. 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 de pendent 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 grow th and suggest that these G1 cyclin dependent kinases might serve as t argets for TGF beta 1-mediated growth arrest. (C) 1994 Wiley-Liss, Inc .