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J Biol Chem. 2000 May 26;275(21):16202-12.

Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling.

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Department of Pathology, State University of New York, Stony Brook, New York 11794-8691, USA.


The mechanism of p53-mediated apoptosis after cellular stress remains poorly understood. Evidence suggests that p53 induces cell death by a multitude of molecular pathways involving activation of target genes and transcriptionally independent direct signaling. Mitochondria play a key role in apoptosis. We show here that a fraction of p53 protein localizes to mitochondria at the onset of p53-dependent apoptosis but not during p53-independent apoptosis or p53-mediated cell cycle arrest. The accumulation of p53 to mitochondria is rapid (within 1 h after p53 activation) and precedes changes in mitochondrial membrane potential, cytochrome c release, and procaspase-3 activation. Immunoelectron microscopy and immuno-fluorescence-activated cell sorter analysis of isolated mitochondria show that the majority of mitochondrial p53 localizes to the membranous compartment, whereas a fraction is found in a complex with the mitochondrial import motor mt hsp70. After induction of ectopic p53 without additional DNA damage in p53-deficient cells, p53 again partially localizes to mitochondria, preceding the onset of apoptosis. Overexpression of anti-apoptotic Bcl-2 or Bcl-xL abrogates stress signal-mediated mitochondrial p53 accumulation and apoptosis but not cell cycle arrest, suggesting a feedback signaling loop between p53 and mitochondrial apoptotic regulators. Importantly, bypassing the nucleus by targeting p53 to mitochondria using import leader fusions is sufficient to induce apoptosis in p53-deficient cells. We propose a model where p53 can contribute to apoptosis by direct signaling at the mitochondria, thereby amplifying the transcription-dependent apoptosis of p53.

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