Published ahead of print on September 29, 2005, doi:10.1165/rcmb.2005-0280OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 174-181 A more recent version of this article appeared on February 1, 2006
Submitted on July 21, 2005 4-Hydroxynonenal Induces Rat Gamma-glutamyl Transpeptidase through MAPK Mediated EpRE/Nrf2 SignalingHongqiao Zhang1,1 Department of Environmental Health Science, University of Alabama at Birmingham, Birmingham, AL, USA, 2 School of Natural Science, University of California at Merced, Merced, CA, USA, 3 Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA, 4 Department of Environmental Health Science, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA, 5 Institute of National de la Sante et la Researche Medicale, Hopital Henri Mondor, Creteil, France * To whom correspondence should be addressed. E-mail: hforman{at}ucmerced.edu.
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-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 located in GGT promoter 5 (GP5 EpRE). 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 Nrf1, 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 p38MAPK, 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.
