title: Inhibition of c-Jun N-terminal kinase pathway improves cell viability in response to oxidant injury.
abstract: Oxidant insults can lead to apoptotic and nonapoptotic cell death. Lung epithelial cells exposed to high levels of oxygen do not die via apoptosis, but through a much slower, morphologically distinct process involving cell and nuclear swelling. In contrast, H2O2 induces a rapid apoptotic cell death. We first assessed the effect of oxidant exposure on activator protein-1 (c-Jun and Fos) and c-Jun N-terminal kinase (JNK) regulation in MLE12 cells. Both oxidants induced c-Jun and Fos expression, albeit with a different pattern of regulation-hyperoxia (95% O2) induced a biphasic response, whereas H2O2 (500 microM) induced a sustained response. We then examined the role of JNK by Western blot, JNK activity assay, and a pull-down assay and observed an identical pattern of regulation. To assess whether JNK functions in a pro-death or pro-survival capacity, we generated stable cell lines that constitutively express a dominant-negative mutation of JNK resulting in significant inhibition of JNK activity. Inhibition of the JNK pathway in this manner prevented hyperoxic and H2O2-induced cell death. These results demonstrate that hyperoxic cell death is pathway-driven and that both modes of death involve the JNK signaling pathway.
authors.affiliation: The CardioPulmonary Research Institute, Winthrop-University Hospital, Suite 505, 222 Station Plaza N, Mineola, NY 11501, USA. liyuchi@hotmail.com
authors.forename: Yuchi
authors.initials: Y
authors.lastname: Li
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arita
authors.forename: Hshi-Chi
authors.initials: HC
authors.lastname: Koo
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Davis
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kazzaz
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016877:Oxidants; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen