gamma-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells.
gamma-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.
Zhang
Hongqiao
H
Department of Environmental Health Science, School of Public Health, University of Alabama at Birmingham, 35294, USA.
Liu
Honglei
H
Dickinson
Dale A
DA
Liu
Rui-Ming
RM
Postlethwait
Edward M
EM
Laperche
Yannick
Y
Forman
Henry Jay
HJ
D021581:Active Transport, Cell Nucleus; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D005723:gamma-Glutamyltransferase; C027576:4-hydroxy-2-nonenal