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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 PA28γ, 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 PA28γ 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 PA28γ in human cancer cells abrogates MDM2‐mediated p53 degradation, increases the activity of p53, and enhances apoptosis. These findings reveal the mechanism by which PA28γ affects apoptosis and proliferation. Manipulation of the level of PA28γ, an approach that would regulate the cellular content of p53, may improve the efficacy of current cancer therapies.

Proteasome activator PA28γ regulates p53 by enhancing its MDM2‐mediated degradation