TGF-β-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-β receptor

Abstract

Transforming growth factor-β1 (TGF-β1) inhibits cell growth in susceptible cells by interacting with a family of protein kinases that control cell cycle progression. In the present study, we investigated the effects of TGF-β1 on cyclin DI expression and activity in COLO-357 human pancreatic cancer cells. TGF-β1 increased cyclin D I mRNA and protein levels. Nuclear runoff transcription and protein synthesis inhibition by cycloheximide revealed that this increase was, in part, due to increased cyclin DI mRNA synthesis. Despite its stimulatory effects on cyclin DI levels, TGF-β1 inhibited cyclin DI-associated kinase activity and the growth of COLO357 cells. Furthermore, suppression of cyclin DI expression with a cyclin DI antisense cDNA resulted in loss of TGF-β1 mediated growth inhibition in association with reduced induction of cyclin DI, p21(Cip)1 and plasminogen activator inhibitor-1 (PAI-1). Concomitantly, there was a marked decrease in the levels of the type I TGF-β receptor (TβRI). Our findings suggest that in some cell types cyclin DI expression may be important for TGF-β1 -mediated signaling and that cyclin DI may be involved in the transcriptional regulation of TβRI.