Mechanisms of TGF-beta-induced cell cycle arrest.

Mitogenic growth factors stimulate cell growth by initiating a signaling cascade leading to the activation of the cyclin-dependent kinases (cdks), phosphorylation of pRb, and subsequent entry of the cell into the S phase. Transforming growth factor-beta (TGF-beta) is a potent antimitogen in a wide variety of cells and is postulated to inhibit cell cycle progression by blocking the late G1 activation of the cdks, thereby preventing pRb phosphorylation and S phase entry. The loss of TGF-beta sensitivity in many transformed cells coupled with recent data demonstrating a deregulation of cyclins, cdks, and cdk inhibitors in many types of cancer has attracted much attention to the molecular mechanism of TGF-beta-mediated growth arrest. Despite these recent advances, further research is required to elucidate how these effects of TGF-beta on the cyclins, cdks, and cdk inhibitors are linked to the TGF-beta receptor complex and the Smad proteins.