Epidermal growth factor-induced hydrogen peroxide production is mediated by dual oxidase 1.
Stimulation of mammalian cells by epidermal growth factor (EGF) elicits complex signaling events, including an increase in hydrogen peroxide (H2O2) production. Understanding the significance of this response is limited by the fact that the source of EGF-induced H2O2 production is unknown. Here we show that EGF-induced H2O2 production in epidermal cell lines is dependent on the agonist-induced calcium signal. We analyzed the expression of NADPH oxidase isoforms and found both A431 and HaCaT cells to express the calcium-sensitive NADPH oxidase, Dual oxidase 1 (Duox1) and its protein partner Duox activator 1 (DuoxA1). Inhibition of Duox1 expression by small interfering RNAs eliminated EGF-induced H2O2 production in both cell lines. We also demonstrate that H2O2 production by Duox1 leads to the oxidation of thioredoxin-1 and the cytosolic peroxiredoxins. Our observations provide evidence for a new signaling paradigm in which changes of intracellular calcium concentration are transformed into redox signals through the calcium-dependent activation of Duox1.
Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; "Momentum" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest 1094, Hungary.
Gábor
G
Sirokmány
Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; "Momentum" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest 1094, Hungary.
Anna
A
Pató
Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; "Momentum" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest 1094, Hungary.
Melinda
M
Zana
Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; "Momentum" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest 1094, Hungary.
Ágnes
Á
Donkó
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest 1122, Hungary.
Adrienn
A
Bíró
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest 1122, Hungary.
Péter
P
Nagy
Department of Physiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary; "Momentum" Peroxidase Enzyme Research Group of the Semmelweis University and the Hungarian Academy of Sciences, Budapest 1094, Hungary. Electronic address: geiszt.miklos@med.semmelweis-univ.hu.
Miklós
M
Geiszt
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D000074623:Dual Oxidases / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D002118:Calcium
Dual oxidase 1; EGF receptor; Hydrogen peroxide; NADPH oxidase; Reactive oxygen species