p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products

Abstract

Activation of the p53 tumour suppressor protein can lead to cell-cycle arrest or apoptosis¹. p53 function is controlled by the mdm2 oncogene product, which targets p53 for proteasomal degradation^2,3. In this report we demonstrate that Mdm2 induces translation of the p53 mRNA from two alternative initiation sites, giving full-length p53 and another protein with a relative molecular mass (M_r) of approximately 47K; we designate this protein as p53/47. This translation induction requires Mdm2 to interact directly with the nascent p53 polypeptide. The alternatively translated p53/47 does not contain the Mdm2-binding site and it lacks the most amino-terminal transcriptional-activation domain of p53. Increased expression of p53/47 stabilizes p53 in the presence of Mdm2, and alters the expression levels of p53-induced gene products. These results show how the interaction of Mdm2 with p53 leads to a change in the ratio of full-length p53 to p53/47 by inducing translation of both p53 proteins and the subsequent selective degradation of full-length p53. Thus, Mdm2 controls the expression levels of p53 through a dual mechanism that involves induction of synthesis and targeting for degradation.