p53-dependent repression of cdk4 synthesis in transforming growth factor-beta-induced G1 cell cycle arrest

Abstract

In summary, TGF-beta induces cell cycle arrest, at least in part, through down-regulation of cdk4 levels and inhibition of cdk2 activity. Thus both of the kinases thought to be responsible for phosphorylation and inactivation of RB in mid to late G1 are affected by the cytokine. Inhibition of cdk4 synthesis occurs at the translational level, is p53 dependent, and requires the 5' UTR of cdk4. David Beach's laboratory has found that TGF-beta also causes the induction of the cdk4-specific inhibitor p15 (a p16 family member). Thus TGF-beta uses two pathways to regulate cdk4 function: decreasing its expression and inhibiting its function. Mutant p53 confers resistance to TGF-beta by preventing cdk4 down-regulation and overcoming the inhibition of cdk2 activity. Work from the laboratories of both Massague and Roberts has shown that the inhibition of cdk2 brought about by TGF-beta is caused by the cdk inhibitor p27.