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Sci. STKE, 8 April 2003
Vol. 2003, Issue 177, p. tw134
[DOI: 10.1126/stke.2003.177.tw134]


APOPTOSIS Mitochondrial p53

The tumor suppressor p53 is best known as a transcription factor that integrates survival and cell death signals. Cell cycle arrest or apoptosis can result from cellular stresses, such as DNA damage, upon p53 activation. Mihara et al. show that p53 targeted to mitochondria is also capable of inducing apoptosis even without the transcriptional activity of p53. In {gamma}-irradiated T thymocytes, p53 accumulated in mitochondria and in the nucleus. Coimmunoprecipitation experiments from cells with DNA damage demonstrated that p53 formed complexes with the antiapoptotic mitochondrial proteins BclXL and Bcl-2, but not with proapoptotic Bax. This p53-Bcl-2 or -BclXL interaction presumably released Bax to allow mitochondrial permeabilization and initiation of apoptosis. In p53-deficient cells, forced targeting of p53 to the mitochondria suppressed colony formation consistent with a mitochondrial pathway for p53 to stimulate apoptosis. Addition of recombinant p53 to isolated mitochondria stimulated cytochrome c release. The interaction site between p53 and BclXL occurred in the DNA binding domain of p53. Thus, mutations in human tumors that disrupt DNA binding may also disrupt the mitochondrial p53 apoptosis pathway. This prediction was confirmed by a lack of coprecipitation of BclXL and mutant p53 from human tumor cell lines or mutant p53 expressed in p53-deficient cells. Thus, p53 appears to contribute to two apoptotic pathways: a nuclear p53 pathway and a mitochondrial p53 pathway.

M. Mihara, S. Erster, A. Zaika, O. Petrenko, T. Chittenden, P. Pancoska, U. M. Moll, p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577-590 (2003). [Online Journal]

Citation: Mitochondrial p53. Sci. STKE 2003, tw134 (2003).

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