TGF-β-induced cell-cycle arrest through the p21waf1/cip1_G1 cyclin/CDKS-p130 pathway in gastric-carcinoma cells

Abstract

Transforming growth factor-β1 (TGF-β) inhibits cell-cycle progression of many types of cells by arresting them in G1/S phase through inhibition of the active cyclin-Cdk complexes that lead to inhibition of Rb phosphorylation. In gastric-cancer cells, SNU16, TGF-β 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. TGF-β also enhanced the stability of p130, suggesting that hypophosphorylation of p130 and increased stability of p130 contribute to p130-mediated G arrest in gastric-cancer cells. Our results demonstrate that p21 and p130 are major downstream targets of TGF-β in gastric-cancer cells and that a p21-G1 cyclin/Cdks-p130/E2F pathway mediates growth inhibition by TGF-β in these cells.