title: p53 mediates autophagy and cell death by a mechanism contingent on Bnip3.
abstract: Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death. Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial ΔΨ(m). This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53--indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3(-/-) mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.
authors: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Erika Yan
authors: EY
authors: Wang
authors: Hongying
authors: H
authors: Gang
authors: Yaron
authors: Y
authors: Aviv
authors: Rimpy
authors: R
authors: Dhingra
authors: Victoria
authors: V
authors: Margulets
authors: Lorrie A
authors: LA
authors: Kirshenbaum
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C505650:BNIP3 protein, rat; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53
keywords: Bnip3; autophagy; cardiac myocytes; cell death; p53