Reddy K B, Hocevar B A, Howe P H
Department of Cell Biology, Cleveland Clinic Research Institute, Ohio 44195.
J Cell Biochem. 1994 Nov;56(3):418-25. doi: 10.1002/jcb.240560318.
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 p33cdk2. This inhibition is not due to TGF beta 1's effect on p33cdk2 synthesis, but rather due to its negative effects on the late G1 phosphorylation of p33cdk2. It is also shown that TGF beta 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.
转化生长因子β1（TGFβ1）在细胞周期的G1期晚期抑制上皮细胞增殖。我们研究了TGFβ1对已知的G1期晚期细胞周期调节因子的影响，试图确定这种生理性抑制剂抑制生长的分子机制。结果表明，TGFβ1抑制p33cdk2的G1期晚期和S期特异性组蛋白H1激酶活性。这种抑制不是由于TGFβ1对p33cdk2合成的影响，而是由于其对p33cdk2的G1期晚期磷酸化的负面影响。还表明，TGFβ抑制G1期晚期细胞周期蛋白A和细胞周期蛋白E相关的组蛋白H1激酶活性。该抑制剂对细胞周期蛋白E的合成没有影响，但显示以细胞周期依赖性方式抑制细胞周期蛋白A的合成。如果将TGFβ1添加到进入G1期超过8小时的细胞中，则它对细胞周期蛋白A的合成没有抑制作用。TGFβ1对G1期晚期细胞周期调节因子的这些作用与其对细胞生长的抑制作用密切相关，表明这些G1期细胞周期蛋白依赖性激酶可能是TGFβ1介导的生长停滞的靶点。
