P53-DEPENDENT REPRESSION OF CDK4 TRANSLATION IN TGF-BETA-INDUCED G(1) CELL-CYCLE ARREST

Transforming growth factor beta 1 (TGF-beta 1) can cause a cell-cycle arrest in G(1). Inhibition of cyclin-dependent kinase 4 (cdk4) synthesis plays a significant role in the mechanism by which this cytokine causes G(1) growth arrest. Deregulated expression of cdk4 confers resistance to TGF-beta 1. Here, we show that TGF-beta 1 down regulates cdk4 expression by inhibiting its translation. Moreover, mutant p53 confers resistance to TGF-beta 1 by interfering with the down-regulation of cdk4 in response to the cytokine. In contrast, we demonstrate that wild-type p53 represses the translation of CDK4. Regulation of cdk4 synthesis by both p53 and TGF-beta 1 is mediated by the 5'-untranslated region of the CDK4 message. Thus, regulation of CDK4 translation may be involved in control of G(1) progression by p53.