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MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation
Akihiro Ito1, Yoshiharu Kawaguchi, Chun-Hsiang Lai
1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Abstract:
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. Here 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 overexpressing 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 ubiquitylated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2-dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups.
Insights
The tumor suppressor p53
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- p53 is a tumor suppressor protein crucial for cellular stress response.
- Post-translational modifications, like acetylation, regulate p53 stability and function.
- MDM2 negatively regulates p300/CBP-mediated p53 acetylation.
Purpose of the Study:
- To investigate the role of MDM2 in p53 deacetylation.
- To identify the mechanism by which MDM2 influences p53 acetylation status.
Main Methods:
- Investigated the interaction between MDM2 and histone deacetylase 1 (HDAC1).
- Assessed p53 deacetylation in cells expressing wild-type and mutant HDAC1.
- Analyzed p53 acetylation, stability, and downstream target gene induction (p21, MDM2) in fibroblasts.
Main Results:
- MDM2 recruits HDAC1 to deacetylate p53 at known acetylated lysine residues.
- HDAC1 complex binds MDM2 independently of p53.
- Dominant-negative HDAC1 mutant restores p53 acetylation, enhancing p53 levels and target gene induction.
- Wild-type HDAC1 and MDM2 act synergistically to deacetylate p53.
Conclusions:
- p53 acetylation promotes its stability and function.
- MDM2-recruited HDAC1 promotes p53 degradation by removing acetyl groups.
- p53 acetylation prevents MDM2-dependent ubiquitylation, thereby stabilizing p53.