title: Differential endoplasmic reticulum stress signaling pathways mediated by iNOS.
abstract: Accumulated misfolded proteins in endoplasmic reticulum (ER) activate ER stress signaling pathways. Here we identified the ER factors that generate ROS molecules. After mouse NIH3T3 cells were treated with either tunicamycin or thapsigargin, oxidative stress was induced. We found inducible nitric oxide synthase (iNOS) was involved in the generation of ROS induced by ER stress. When thapsigargin-treated cells were pre-treated with iNOS inhibitors 1400W or L-canavanine, their ER stress-induced oxidative stress was almost totally abolished. This effect was not seen in the cells treated with tunicamycin. Therefore, iNOS appears to mediate the ER stress subpathway caused by Ca(2+) efflux. To the contrary, after we treated the cells with the 26S proteasome inhibitors lactacystin or MG-132, the UPR-induced oxidative stress dramatically increased, indicating that clearing misfolded proteins from the ER lumen reduced the oxidative stress. Therefore, the oxidative stress induced by ER stress signaling is mediated through both iNOS-dependent and -independent subpathways.
authors.affiliation: Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Hsieh
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
authors.forename: Wenya
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D041681:NIH 3T3 Cells; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress; D015398:Signal Transduction; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D014415:Tunicamycin; D052247:Nitric Oxide Synthase Type II