p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2

Ito, Akihiro; Chun-Hsiang Lai; Xuan Zhao; Shin'ichi Saito; Hamilton, Maria H.; Appella, Ettore; Tso-Pang Yao
March 2001
EMBO Journal;3/15/2001, Vol. 20 Issue 6, p1331
Academic Journal
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 p19ARF, indicating that regulation of acetylation is a central target of the p53-MDM2-p19ARF 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 modifi cation for p53 function.


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