TGF-beta-induced cell-cycle arrest through the p21(WAF1)/(CIP1)-G1 cyclin/Cdks-p130 pathway in gastric-carcinoma cells

Transforming growth factor-beta 1 (TGF-beta) inhibits cell-cycle progressio n of many types of cells by arresting them in G(1)/S phase through inhibiti on of the active cyclin-Cdk complexes that lead to inhibition of Rb phospho rylation. In gastric-cancer cells, SNU16, TGF-P treatment induced enhanced expression of p21(WAF1/CIP1) (p21), which inhibited the kinase activity of cyclin-D- and cyclin-E-associated Cdks and blocked p130 phosphorylation. TG F-beta also enhanced the stability of p130, suggesting that hypophosphoryla tion of p130 and increased stability of p130 contribute to p130-mediated G( 1) arrest in gastric-cancer cells. Our results demonstrate that p21 and p13 0 are major downstream targets of TGF-beta in gastric-cancer cells and that a p21-G(1) cyclin/Cdks-p130/E2F pathway mediates growth inhibition by TGF- beta in these cells. Int. J. Cancer 83:512-517, 1999. (C) 1999 Wiley-Liss, Inc.