Abstract

Downregulation of p53 by MDM2-mediated proteasomal degradation makes cells resistant to apoptosis. The MDM2–p53 interaction is well characterized, but the mechanisms that regulate the interaction are not well understood. Here, we show that PA28, a proteasome activator that inhibits apoptosis and promotes cell cycle progression through unknown mechanisms, exerts an effect as a cofactor in the MDM2–p53 interaction. The polymer form of PA28 interacts with both MDM2 and p53 proteins and facilitates their physical interaction. This promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. Elimination of endogenous PA28 in human cancer cells abrogates MDM2-mediated p53 degradation, increases the activity of p53, and enhances apoptosis. These findings reveal the mechanism by which PA28 affects apoptosis and proliferation. Manipulation of the level of PA28, an approach that would regulate the cellular content of p53, may improve the efficacy of current cancer therapies.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

The EMBO Journal is published by Nature Publishing Group on behalf of European Molecular Biology Organization

This article is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.5 Licence