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4-Hydroxynonenal Induces Rat -Glutamyl Transpeptidase through Mitogen-Activated Protein Kinase–Mediated Electrophile Response Element/Nuclear Factor Erythroid 2–Related Factor 2 Signaling

Department of Environmental Health Science, School of Public Health, and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama; School of Natural Science, University of California at Merced, Atwater, California; and Institut National de la Sante et de la Researche Medicale, Hopital Henri Mondor, Creteil, France

Correspondence and requests for reprints should be addressed to Dr. Henry Jay Forman, School of Natural Science, University of California at Merced, Atwater, CA 95301. E-mail: hforman{at}ucmerced.edu

-Glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5'-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epithelial cells, and that it could be induced by 4-hydroxynonenal (HNE) through the electrophile response element (EpRE) located in GGT promoter 5 (GP5). Here, we report transcription factors binding to GP5 EpRE and the involved signaling pathways. Immunodepletion gel shift assays demonstrated that GP5 EpRE bound JunB, c-Jun, FosB, and Fra2 from unstimulated cells, and that after exposure to HNE, EpRE binding complexes contained nuclear factor erythroid 2–related factor (Nrf) 1, Nrf2, JunB, c-Jun, FosB, c-Fos, Fra1, and Fra2. HNE-induced binding of Nrf2 and c-Jun in GP5 EpRE was confirmed by chromatin immunoprecipitation assays. Using reporter assays and specific inhibitors, we found that HNE induction of rat GGT mRNA V-2 was dependent on activation of extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not protein kinase C or phosphatidylinositol 3-kinase. Pretreatment with ERK and p38MAPK inhibitors also blocked HNE-increased EpRE binding. HNE-increased nuclear content of Nrf1, Nrf2, and c-Jun in L2 cells was partially blocked by inhibition of either ERK1/2 or p38MAPK and completely blocked by simultaneous inhibition of both MAPKs. In conclusion, HNE induces GGT mRNA V-2 through altered EpRE transcription factor binding mediated by both ERK and p38MAPK.

Key Words: electrophile response element • -glutamyl transpeptidase • glutathione • 4-hydroxynonenal • nuclear factor erythroid 2–related factor 2

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