γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

• Published in: Free radical biology & medicine 2006-04, Vol.40 (8), p.1281-1292
• Main Authors: Zhang, Hongqiao, Liu, Honglei, Dickinson, Dale A., Liu, Rui-Ming, Postlethwait, Edward M., Laperche, Yannick, Forman, Henry Jay
• Format: Article
• Language: English
• Subjects: 4-Hydroxy-2-nonenal; Active Transport, Cell Nucleus; Aldehydes - pharmacology; Animals; Base Sequence; Cell Line; Epithelial Cells - drug effects; Epithelial Cells - metabolism; EpRE; Free radicals; gamma-Glutamyltransferase - genetics; gamma-Glutamyltransferase - metabolism; Gene Expression; Glutathione; Molecular Sequence Data; Mutation - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Promoter Regions, Genetic - genetics; Rats; Response Elements; RNA, Messenger - genetics; Signal Transduction - drug effects; Tissue distribution; γ-Glutamyl transpeptidase
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2005.11.005

γ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNA V is controlled by promoter 5. Previously we found that GGT mRNA V-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal- and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNA V-2 was expressed in many tissues in rat. Taken together, GGT mRNA V-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.