Li C Y, Suardet L, Little J B
Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts 02115.
J Biol Chem. 1995 Mar 10;270(10):4971-4. doi: 10.1074/jbc.270.10.4971.
Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression of many types of human cells by arresting them in the G1 phase of the cell cycle. The arrest is mediated through interactions of various cyclin-dependent protein kinases (CDKs) and their inhibitors. We demonstrate that treatment with TGF-beta induces increased levels of WAF1/Cip1/p21, a potent inhibitor of various cyclin-CDK kinase activities, in two colon cancer cell lines (LS1034 and LS513), which are sensitive to TGF-beta-induced growth arrest. The induction in at least one of these cell lines (LS1034,p53-) is p53-independent. No WAF1 induction was observed after TGF-beta treatment in a third cell line (HT-29), which is completely insensitive to the cytoinhibitory effect of TGF-beta. In both LS513 and LS1034, WAF1 induction correlated with reduced cyclin E-associated kinase activity in vitro and suppression of the retinoblastoma susceptibility gene (Rb) protein phosphorylation in vivo. In addition, WAF1 was physically associated with cyclin E in the two sensitive cell lines. These results suggest that WAF1/Cip1/p21 is a mediator of cellular sensitivity to TGF-beta.
转化生长因子-β（TGF-β）通过将多种人类细胞阻滞在细胞周期的G1期来抑制其细胞周期进程。这种阻滞是通过各种细胞周期蛋白依赖性蛋白激酶（CDK）及其抑制剂之间的相互作用介导的。我们证明，在对TGF-β诱导的生长阻滞敏感的两种结肠癌细胞系（LS1034和LS513）中，用TGF-β处理可诱导WAF1/Cip1/p21水平升高，WAF1/Cip1/p21是多种细胞周期蛋白-CDK激酶活性的有效抑制剂。在这些细胞系中的至少一种（LS1034，p53-）中，这种诱导是不依赖p53的。在对TGF-β的细胞抑制作用完全不敏感的第三种细胞系（HT-29）中，TGF-β处理后未观察到WAF1的诱导。在LS513和LS1034中，WAF1的诱导与体外细胞周期蛋白E相关激酶活性的降低以及体内视网膜母细胞瘤易感基因（Rb）蛋白磷酸化的抑制相关。此外，在这两种敏感细胞系中，WAF1与细胞周期蛋白E存在物理关联。这些结果表明，WAF1/Cip1/p21是细胞对TGF-β敏感性的介导因子。
