P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis.
Asbestos causes pulmonary toxicity in part by generating reactive oxygen species that cause DNA damage. We previously showed that the mitochondria-regulated (intrinsic) death pathway mediates alveolar epithelial cell (AEC) DNA damage and apoptosis. Because p53 regulates the DNA damage response in part by inducing intrinsic cell death, we determined whether p53-dependent transcriptional activity mediates asbestos-induced AEC mitochondrial dysfunction and apoptosis. We show that inhibitors of p53-dependent transcriptional activation (pifithrin and type 16-E6 protein) block asbestos-induced AEC mitochondrial membrane potential change (DeltaPsim), caspase 9 activation, and apoptosis. We demonstrate that asbestos activates p53 promoter activity, mRNA levels, protein expression, and Bax and p53 mitochondrial translocation. Further, pifithrin, E6, phytic acid, or rho(0)-A549 cells (cells incapable of mitochondrial reactive oxygen species production) block asbestos-induced p53 activation. Finally, we show that asbestos augments p53 expression in cells at the bronchoalveolar duct junctions of rat lungs and that phytic acid prevents this. These data suggest that p53-dependent transcription pathways mediate asbestos-induced AEC mitochondria-regulated apoptosis. This suggests an important interactive effect between p53 and the mitochondria in the pathogenesis of asbestos-induced pulmonary toxicity that may have broader implications for our understanding of pulmonary fibrosis and lung cancer.
Panduri
Vijayalakshmi
V
Northwestern University Feinberg School of Medicine, Pulmonary and Critical Care Medicine, McGaw M-2300, 240 E. Huron St., Chicago, IL 60611-3010, USA.
Surapureddi
Sailesh
S
Soberanes
Saul
S
Weitzman
Sigmund A
SA
Chandel
Navdeep
N
Kamp
David W
DW
D000818:Animals; D017209:Apoptosis; D017639:Asbestos, Amosite / Q000633:toxicity*; D001195:Asbestosis / Q000378:metabolism; D052160:Benzothiazoles; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D010833:Phytic Acid / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D052160:Benzothiazoles; C068651:E6 protein, Human papillomavirus type 16; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D009856:Oncogene Proteins, Viral; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D017639:Asbestos, Amosite; D014050:Toluene; D010833:Phytic Acid; C121565:pifithrin; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases