H2O2-dependent activation of GCLC-ARE4 reporter occurs by mitogen-activated protein kinase pathways without oxidation of cellular glutathione or thioredoxin-1

被引:76
作者
Go, YM
Gipp, JJ
Mulcahy, RT
Jones, DP [1 ]
机构
[1] Emory Univ, Rollins Res Ctr 4131, Dept Med, Sch Med,Div Cardiol, Atlanta, GA 30322 USA
[2] Emory Univ, Ctr Clin & Mol Nutr, Atlanta, GA 30322 USA
[3] Univ Wisconsin, Sch Med, Dept Surg, Madison, WI 53792 USA
[4] Univ Wisconsin, Sch Med, Dept Pharmacol, Madison, WI 53792 USA
关键词
D O I
10.1074/jbc.M307547200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The gp91(phox) 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.
引用
收藏
页码:5837 / 5845
页数:9
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