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

@article{Chipuk2004DirectAO,
  title={Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis},
  author={Jerry Edward Chipuk and Tomomi Kuwana and Lisa Bouchier-Hayes and Nathalie M. Droin and Donald D. Newmeyer and Martin Schuler and Douglas R. Green},
  journal={Science},
  year={2004},
  volume={303},
  pages={1010 - 1014}
}
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-2protein 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… 

Cytoplasmic p53: Bax and Forward

Data suggest that cytoplasmic p53 functions analogously to the BH3-only proteins, a subset of pro-apoptotic Bcl-2 proteins.

The DNA-binding domain mediates both nuclear and cytosolic functions of p53

The studies define the contributions of cytosolic p53 to UV irradiation–induced apoptosis and provide opportunities to explore its contributions to other p53-dependent apoptotic signaling pathways.

Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins

The data show that the induction of apoptosis by inhibition of the anti-apoptotic BCL-2 repertoire requires “covert” levels of direct activators of BAX and BAK at the OMM.

Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL

It is shown that the tumor suppressor p53 contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL and provides a death signal downstream of anti-apoptotic proteins inhibition.

Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL

It is shown that the tumor suppressor p53 contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL and provides a death signal downstream of anti-apoptotic proteins inhibition.

p53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria*

A caspase-dependent cleavage of p53 resulting in the generation of four fragments, two of which lack a nuclear localization signal and consequently localize to cytosol supports the model whereby cytosolic p53 exerts major functions in apoptosis and also suggests the presence of a positive feedback loop in which activated caspases cleave p53 to augment mitochondrial membrane depolarization.

Regulation of Mitochondrial Apoptotic Events by p53-mediated Disruption of Complexes between Antiapoptotic Bcl-2 Members and Bim*

It is demonstrated that apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim, and an inverse correlation between the binding levels of p53 and Bim to Mcl-1 is demonstrated.

Serine 392 phosphorylation modulates p53 mitochondrial translocation and transcription-independent apoptosis

Observations support the premise that serine 392 phosphorylation of p53 influences its mitochondrial translocation and transcription-independent apoptotic function.

Transcription-independent pro-apoptotic functions of p53.

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