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Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis

Jerry E Chipuk1, Tomomi Kuwana, Lisa Bouchier-Hayes

  • 1Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.

Science (New York, N.Y.)
|February 14, 2004
PubMed

Insights

The tumor suppressor p53 protein induces apoptosis by directly activating the Bax protein in the cell

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor p53 is crucial for preventing cancer.
  • p53's anti-cancer effects are mainly mediated by inducing programmed cell death (apoptosis).

Purpose of the Study:

  • To investigate the mechanism by which p53 induces apoptosis.
  • To determine the role of p53's localization and direct interactions in apoptosis induction.

Main Methods:

  • Studied the localization of endogenous p53 (wild-type and trans-activation-deficient).
  • Assessed the direct activation of the Bcl-2-associated X protein (Bax) by p53.
  • Investigated the release of other proapoptotic proteins sequestered by Bcl-extra-large (Bcl-xL).

Main Results:

  • Cytosolic localization of p53 was essential and sufficient for apoptosis.
  • p53 directly activated Bax, leading to mitochondrial permeabilization and apoptosis.
  • p53 released proapoptotic proteins from Bcl-xL inhibition.
  • Transcription-independent activation of Bax by p53 occurred rapidly and at low concentrations.

Conclusions:

  • Cytosolic p53 acts similarly to BH3-only proteins, directly activating Bax to initiate apoptosis.
  • This mechanism provides a novel understanding of p53's role in cancer suppression.

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