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Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex

Nature Cell Biology volume 6, pages 443–450 (2004)Cite this article

Abstract

The tumour suppressor activity of the p53 protein has been explained by its ability to induce apoptosis in response to a variety of cellular stresses1,2. Thus, understanding the mechanism by which p53 functions in the execution of cell death pathways is of considerable importance in cancer biology. Recent studies have indicated that p53 has a direct signalling role at mitochondria in the induction of apoptosis3,4,5,6, although the mechanisms involved are not completely understood. Here we show that, after cell stress, p53 interacts with the pro-apoptotic mitochondrial membrane protein Bak. Interaction of p53 with Bak causes oligomerization of Bak and release of cytochrome c from mitochondria. Notably, we show that formation of the p53–Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl2-family member Mcl1. These results are consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak.

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Figure 1: Bak and p53 interact.
Figure 2: p53 binds to Bak in vitro.
Figure 3: p53 induces oligomerization of Bak.
Figure 4: Characterization of the Mcl1–Bak interaction.
Figure 5: The p53–Bak interaction correlates with disruption of the Mcl1–Bak interaction.

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Acknowledgements

We thank T. Lindsten and C. Thompson for the Bak+/+ and Bak−/− MEFs, and J. M. Hardwick for Bak and Bax constructs. This work was supported by US Public Health Service National Institutes of Health grants CA089240, CA080854 and 5-T32-HD07516, as well as a grant from the Department of the Army (DAMD-17-02-1-0383).

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Authors and Affiliations

  1. Department of Genetics, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, 19104, PA, USA

    J. I-Ju Leu & Donna L. George

  2. Department of Pharmacology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111, PA, USA

    Patrick Dumont, Michael Hafey & Maureen E. Murphy

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Correspondence to Donna L. George.

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Leu, JJ., Dumont, P., Hafey, M. et al. Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nat Cell Biol 6, 443–450 (2004). https://doi.org/10.1038/ncb1123

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