4-Hydroxynonenal induces rat gamma-glutamyl transpeptidase through mitogen-activated protein kinase-mediated electrophile response element/nuclear factor erythroid 2-related factor 2 signaling.
Gamma-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.
Zhang
Hongqiao
H
Department of Environmental Health Science, School of Public Health, University of Alabama at Birmingham, USA.
Liu
Honglei
H
Iles
Karen E
KE
Liu
Rui-Ming
RM
Postlethwait
Edward M
EM
Laperche
Yannick
Y
Forman
Henry Jay
HJ
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020218:Response Elements; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000187:drug effects / Q000378:metabolism*
D000447:Aldehydes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D011725:Pyridines; D014157:Transcription Factors; D005723:gamma-Glutamyltransferase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one