期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 44, 期 5, 页码 868-881出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.11.020
关键词
NADPH oxidase; NOX5; hydrogen peroxide; signaling; c-Abl; superoxide; calcium; free radicals
资金
- NCI NIH HHS [P30 CA 054174, P30 CA054174] Funding Source: Medline
- NIAID NIH HHS [R37 AI020866, R01 AI034879, R01 AI020866, R01 AI020866-18, R56 AI034879, AI 020866, AI 034879] Funding Source: Medline
- NIA NIH HHS [P01 AG 019316, P30 AG013319, R01 AG019519, AG 019519, P30 AG 013319, P01 AG019316] Funding Source: Medline
- BLRD VA [I01 BX000513] Funding Source: Medline
We investigated the mechanism of H2O2 activation of the Ca2+-regulated NADPH oxidase NOX5. H2O2 induced a transient, dose-dependent increase in superoxide production in K562 cells expressing NOX5. Confocal studies demonstrated that the initial calcium influx generated by H2O2 is amplified by a feedback mechanism involving NOX5-dependent superoxide production and H2O2. H2O2 NOX5 activation was inhibited by extracellular Ca2+ chelators, a pharmacological inhibitor of c-Abl, and overexpression of kinase-dead c-Abl. Transfected kinase-active GFP-c-Abl colocalized with vesicular sites of superoxide production in a Ca2+-dependent manner. In contrast to H2O2, the Ca2+ ionophore ionomycin induced NOX5 activity independent of c-Abl. Immunoprecipitation of cell lysates revealed that active GFP-c-Abl formed oligomers with endogenous c-Abl and that phosphorylation of both proteins was increased by H2O2 treatment. Furthermore, H2O2-induced NOX5 activity correlated with increased localization of c-Abl to the membrane fraction, and NOX5 proteins could be coimmunoprecipitated with GFP-Abl proteins. Our data demonstrate for the first time that NOX5 is activated by c-Abl through a Ca2+-mediated, redox-dependent signaling pathway and suggest a functional association between NOX5 NADPH oxidase and c-Abl. (c) 2007 Elsevier Inc. All rights reserved.
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