Reactive oxygen species mediate ERK activation through different Raf-1-dependent signaling pathways following cerebral ischemia.
Production of reactive oxygen species (ROS) results in up-regulation of the extracellular signal-regulated kinase (ERK) cascade in response to numerous stimuli. Cerebral ischemia induces calcium-dependent kinase activation followed by ROS production. Here, we examined how ROS mediates the activation of ERK following cerebral ischemia in the rat hippocampus. We found that alpha-tocopherol, a free radical scavenger, attenuated the initial, robust activation of ERK by inhibiting Raf-1 dephosphorylation at Ser259. Alpha-tocopherol also down-regulated the second and mild activation of ERK through inhibition of Src-dependent phosphorylation of Raf-1 at Tyr340/341. Our results suggest that ROS production mediates the biphasic activation of ERK through different signaling cascades following post-ischemic reperfusion. Mediation of these signaling pathways involves changes in Raf-1 phosphorylation at different sites.
Wu
Hui-wen
HW
Jiangsu Provincial Key Laboratories of Human Functional Genomics, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, Jiangsu, 210029, China.
Li
Hong-fu
HF
Wu
Xiang-yang
XY
Zhao
Jie
J
Guo
Jun
J
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D024502:alpha-Tocopherol / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D019061:src-Family Kinases; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D024502:alpha-Tocopherol