H2O2-dependent activation of GCLC-ARE4 reporter occurs by mitogen-activated protein kinase pathways without oxidation of cellular glutathione or thioredoxin-1.
The gp91phox homologue Nox1 produces H2O2, which induces cell growth, transformation, and tumorigenicity. However, it has not been clear whether H2O2 effects are mediated indirectly via a generally oxidizing cellular environment or whether H2O2 more directly targets specific signaling pathways. Here, we investigated signaling by H2O2 induced by Nox1 overexpression using a luciferase reporter regulated by the antioxidant response element ARE4. Surprisingly, Nox1-derived H2O2 activated the reporter gene 15-fold with no effect on the redox state of the major thiol antioxidant substances, glutathione and thioredoxin. H2O2 signaling to ARE4 was mediated by activation of both the c-Jun N-terminal kinase and ERK1/2 pathways modulated by Ras. Thus, "redox signaling" resulting in kinase signaling pathways is distinct from "oxidative stress," and is mediated by discrete, localized redox circuitry.
Go
Young-Mi
YM
Department of Medicine, Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Gipp
Jerry J
JJ
Mulcahy
R Timothy
RT
Jones
Dean P
DP
D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D018929:Cell Culture Techniques; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D017930:Genes, Reporter; D005949:Glucose Oxidase / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D020218:Response Elements; D015398:Signal Transduction; D013879:Thioredoxins / Q000737:chemistry* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; C491200:Txndc2 protein, mouse; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D002374:Catalase; D008156:Luciferases; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D010100:Oxygen