Differential endoplasmic reticulum stress signaling pathways mediated by iNOS.
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.
Hsieh
Yi-Hsuan
YH
Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Su
Ih-Jen
IJ
Lei
Huan-Yao
HY
Lai
Ming-Derg
MD
Chang
Wen-Wei
WW
Huang
Wenya
W
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
D014415:Tunicamycin; D052247:Nitric Oxide Synthase Type II