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.
Hocevar
B A
BA
Department of Cell Biology, Cleveland Clinic Research Institute, Ohio 44195, USA.
Howe
P H
PH
D000818:Animals; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins; D004791:Enzyme Inhibitors; D016193:G1 Phase; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016213:Cyclins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D016212:Transforming Growth Factor beta; D018844:Cyclin-Dependent Kinases