Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis

TLDR

The tumor suppressor p53 exerts its anti‑neoplastic activity primarily through induction of apoptosis. The study proposes that cytosolic accumulation of p53 can activate Bax and trigger apoptosis. p53 directly activates Bax in the cytosol, acting like a BH3‑only protein to permeabilize mitochondria. Cytosolic p53 is necessary and sufficient for apoptosis, directly activates Bax to permeabilize mitochondria, releases proapoptotic proteins sequestered by Bcl‑xL, and does so with kinetics and concentrations comparable to activated Bid.

Abstract

The tumor suppressor p53 exerts its anti-neoplastic activity primarily through the induction of apoptosis. We found that cytosolic localization of endogenous wild-type or trans-activation-deficient p53 was necessary and sufficient for apoptosis. p53 directly activated the proapoptotic Bcl-2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. p53 also released both proapoptotic multidomain proteins and BH3-only proteins [Proapoptotic Bcl-2 family proteins that share only the third Bcl-2 homology domain (BH3)] that were sequestered by Bcl-xL. The transcription-independent activation of Bax by p53 occurred with similar kinetics and concentrations to those produced by activated Bid. We propose that when p53 accumulates in the cytosol, it can function analogously to the BH3-only subset of proapoptotic Bcl-2 proteins to activate Bax and trigger apoptosis.