Functional Analysis of p53 Acetylation in Prostate Tumor Suppression.

摘要

The tumor suppressor p53 becomes acetylated upon its activation. We show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Fibroblasts over- expressing a dominant negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation, increased levels of p53, and a more pronounced induction of p21 and MDM2. These results indicate that acetylation promotes p53 stability and function. As the acetylated p53 lysine residues overlap with those that are ubiquitinated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2-dependent ubiquitination, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups. We also found that acetylation regulates p53 subcellular localization by promoting p53 nuclear export. Thus, acetylation controls p53 function at several levels. Finally, we report that MDM2 is also subject to acetylation. We present evidence that acetylation-deficient MDM2 mutant is defective in promoting p53 deacetylation and degradation. Our studies reveal protein acetylation as an important mechanism in regulating the p53-MDM2 tumor suppressor network.