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Published ahead of print on December 15, 2005, doi:10.1165/rcmb.2005-0352OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 4, April 2006, 443-452

A more recent version of this article appeared on April 1, 2006
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Submitted on September 13, 2005
Revised on December 13, 2005

P53 Mediates Amosite Asbestos Induced Alveolar Epithelial Cell Mitochondria-regulated Apoptosis

Vijayalakshmi Panduri1, Sailesh Surapureddi2, Saul Soberanes1, Sigmund A Weitzman3, Navdeep Chandel1, and David W Kamp1*

1 Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, Northwestern University Feinburg School of Medicine and Veterans Administration Chicago Health Care System, Chicago, IL, USA, 2 Department of Pathology, Northwestern University Feinburg School of Medicine and Veterans Administration Chicago Health Care System, Chicago, IL, USA, 3 Division of Hematology-Oncology, Northwestern University Feinburg School of Medicine and Veterans Administration Chicago Health Care System, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: d-kamp{at}northwestern.edu.

Asbestos causes pulmonary toxicity in part by generating reactive oxygen species (ROS) that cause DNA damage. We previously showed that the mitochondria-regulated (intrinsic) death pathway mediates alveolar epithelial cell (AEC) DNA damage and apoptosis. Since 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 ({Delta}{Psi}m), caspase 9 activation, and apoptosis. We demonstrate that asbestos activates p53 promoter activity, mRNA levels and protein expression as well as Bax and p53 mitochondrial translocation. Further, pifithrin, E6, phytic acid, or {rho}0-A549 cells (cells incapable of mitochondrial ROS production) block asbestos-induced p53 activation. Finally, we show that asbestos augments p53 expression in cells at the broncho-alveolar duct junctions of rat lungs and that phytic acid prevents this. These data firmly implicate 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.




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