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p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2
1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Abstract:
The tumor suppressor p53 is activated in response to many types of cellular and environmental insults via mechanisms involving post-translational modification. Here we demonstrate that, unlike phosphorylation, p53 invariably undergoes acetylation in cells exposed to a variety of stress-inducing agents including hypoxia, anti-metabolites, nuclear export inhibitor and actinomycin D treatment. In vivo, p53 acetylation is mediated by the p300 and CBP acetyltransferases. Overexpression of either p300 or CBP, but not an acetyltransferase-deficient mutant, efficiently induces specific p53 acetylation. In contrast, MDM2, a negative regulator of p53, actively suppresses p300/CBP-mediated p53 acetylation in vivo and in vitro. This inhibitory activity of MDM2 on p53 acetylation is in turn abrogated by tumor suppressor p19(ARF), indicating that regulation of acetylation is a central target of the p53-MDM2-p19(ARF) feedback loop. Functionally, inhibition of deacetylation promotes p53 stability, suggesting that acetylation plays a positive role in the accumulation of p53 protein in stress response. Our results provide evidence that p300/CBP-mediated acetylation may be a universal and critical modification for p53 function.
Insights
p53 acetylation is a key stress response, unlike phosphorylation. Acetylation by p300/CBP enhances p53 stability, regulated by MDM2 and p19ARF.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- The tumor suppressor p53 is crucial for cellular defense against various stresses.
- p53 activation involves post-translational modifications, including phosphorylation and acetylation.
- Understanding p53 regulation is vital for cancer research.
Purpose of the Study:
- To investigate the role of p53 acetylation in cellular stress response.
- To identify the enzymes responsible for p53 acetylation and their regulators.
- To elucidate the functional significance of p53 acetylation in p53 protein accumulation.
Main Methods:
- Exposure of cells to various stress-inducing agents (hypoxia, anti-metabolites, etc.).
- In vivo and in vitro assays to assess p53 acetylation.
- Overexpression of p300, CBP, and MDM2, including mutant forms.
- Analysis of the p53-MDM2-p19ARF feedback loop.
Main Results:
- p53 consistently undergoes acetylation, not phosphorylation, under diverse cellular stresses.
- p300 and CBP acetyltransferases mediate p53 acetylation in vivo.
- MDM2 inhibits p300/CBP-mediated p53 acetylation, an effect reversed by p19ARF.
- Inhibition of deacetylation enhances p53 stability, indicating acetylation's role in p53 accumulation.
Conclusions:
- p300/CBP-mediated acetylation is a universal and critical modification for p53 function during stress.
- Acetylation plays a positive role in stress-induced p53 protein accumulation.
- The p53-MDM2-p19ARF pathway regulates p53 acetylation, highlighting its importance in tumor suppression.