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

AUTOR(ES)

Ito, Akihiro

FONTE

Oxford University Press

RESUMO

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.

Documentos Relacionados

• MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins
• mdm2 expression is induced by wild type p53 activity.
• Regulation of p53 and MDM2 Activity by MTBP
• Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation
• Hypophosphorylation of Mdm2 Augments p53 Stability