TGF-beta-1 up-regulates cyclin D1 expression in COLO-357 cells, whereas suppression of cyclin D1 levels is associated with down-regulation of the type I TGF-beta receptor

Transforming growth factor-beta 1 (TGF-beta 1) inhibits cell growth in susc eptible cells by interacting with a family of protein kinases that control cell cycle progression. In the present study, we investigated the effects o f TGF-beta 1 on cyclin DI expression and activity in COLO-357 human pancrea tic cancer cells. TGF-beta 1 increased cyclin DI mRNA and protein levels. N uclear runoff transcription and protein synthesis inhibition by cycloheximi de revealed that this increase was, in part, due to increased cyclin DI mRN A synthesis. Despite its stimulatory effects on cyclin DI levels, TGF-beta 1 inhibited cyclin D1-associated kinase activity and the growth of COLO-357 cells. Furthermore, suppression of cyclin DI expression with a cyclin DI a ntisense cDNA resulted in loss of TGF-beta 1 mediated growth inhibition in association with reduced induction of cyclin DI, p21(Cip1) and plasminogen activator inhibitor-1 (PAI-I). Concomitantly, there was a marked decrease i n the levels of the type I TGF-beta receptor (T beta RI), Our findings sugg est that in some cell types cyclin DI expression may be important for TGF-b eta 1-mediated signaling and that cyclin DI may be involved in the transcri ptional regulation of T beta RI, (C) 1999 Wiley-Liss, Inc.