Functional Analysis of p53 Acetylation in Prostate Tumor Suppression

摘要

The tumor suppressor p53 is stabilized and activated in response to cellular stress through post translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. 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. Ectopic expression of a dominant negative HDAC1 mutant restores p53 acetylation in the presence of MDM2, whereas wild-type HDAC1 and MDM2 deacetylate p53 synergistically. 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.