Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling.
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.
Marchenko
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ND
Department of Pathology, State University of New York, Stony Brook, New York 11794-8691, USA.
Zaika
A
A
Moll
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UM
D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D018840:HSP70 Heat-Shock Proteins; D021382:Protein Sorting Signals; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein