Suppression of p53 activity by Siva1.

ABSTRACT: The tumor suppressor p53 induces potent anti-proliferative responses in stressed cells; in unstressed cells this ability of p53 is restrained by Hdm2. Expression of Hdm2 is also induced by p53, thereby establishing feedback inhibition. Regulation of the p53-Hdm2 interaction and the feedback inhibition of p53 are not well understood. Here, we show that the p53-Hdm2 interaction in unstressed cells is promoted by Siva1, which, like Hdm2, is the product of a p53 target gene. Siva1 binds to both p53 and Hdm2 through distinct regions and enhances Hdm2-mediated p53 ubiquitination and degradation. Siva1 strongly inhibits p53-mediated gene expression and apoptosis. In xenograft mouse models, downregulation of Siva1 markedly inhibits tumor formation because of the activation of p53. On DNA damage, t

SUBMITTER: Du W 

PROVIDER: S-EPMC2883715 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature