Nrf1 and Nrf2 Regulate Rat Glutamate-Cysteine Ligase Catalytic Subunit Transcription Indirectly via NF-κB and AP-1
Open Access
- 1 July 2005
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 25 (14), 5933-5946
- https://doi.org/10.1128/mcb.25.14.5933-5946.2005
Abstract
Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by Nrf1 and Nrf2. tert-Butylhydroquinone (TBH) induces human GCLC via Nrf2-mediated trans activation of the antioxidant-responsive element (ARE). Interestingly, TBH also induces rat GCLC, but the rat GCLC promoter lacks ARE. This study examined the role of Nrf1 and Nrf2 in the transcriptional regulation of rat GCLC. The baseline and TBH-mediated increase in GCLC mRNA levels and rat GCLC promoter activity were lower in Nrf1 and Nrf2 null (F1 and F2) fibroblasts than in wild-type cells. The basal protein and mRNA levels and nuclear binding activities of c-Jun, c-Fos, p50, and p65 were lower in F1 and F2 cells and exhibited a blunted response to TBH. Lower c-Jun and p65 expression also occurs in Nrf2 null livers. Levels of other AP-1 and NF-κB family members were either unaffected (i.e., JunB) or increased (i.e., Fra-1). Overexpression of Nrf1 and Nrf2 in respective cells restored the rat GCLC promoter activity and response to TBH but not if the AP-1 and NF-κB binding sites were mutated. Fra-1 overexpression lowered endogenous GCLC expression and rat GCLC promoter activity, while Fra-1 antisense had the opposite effects. In conclusion, Nrf1 and Nrf2 regulate rat GCLC promoter by modulating the expression of key AP-1 and NF-κB family members.Keywords
This publication has 47 references indexed in Scilit:
- Induction of Human Methionine Adenosyltransferase 2A Expression by Tumor Necrosis Factor αPublished by Elsevier BV ,2003
- Nrf1 Is Critical for Redox Balance and Survival of Liver Cells during DevelopmentMolecular and Cellular Biology, 2003
- Combined Effects of Tumor Promoters and Serum on Proliferin mRNA Induction: A Biomarker Sensitive to Saccharin, 2,3,7,8-Tcdd, and Other Compounds at Minimal Concentrations Promoting C3H/10T1/2 Cell TransformationJournal of Toxicology and Environmental Health, Part A, 2003
- Role of AP-1 in the Coordinate Induction of Rat Glutamate-cysteine Ligase and Glutathione Synthetase bytert-ButylhydroquinonePublished by Elsevier BV ,2002
- Identification of a Variant Antioxidant Response Element in the Promoter of the Human Glutamate-Cysteine Ligase Modifier Subunit GenePublished by Elsevier BV ,2002
- Cloning and characterization of the 5′-flanking region of the rat glutamate-cysteine ligase catalytic subunitBiochemical Journal, 2001
- Effect of Thioacetamide on the Hepatic Expression of γ-Glutamylcysteine Synthetase Subunits in the RatToxicology and Applied Pharmacology, 1999
- An Electrophile Responsive Element (EpRE) Regulates β-Naphthoflavone Induction of the Human γ-Glutamylcysteine Synthetase Regulatory Subunit GenePublished by Elsevier BV ,1998
- DNA binding and IκB inhibition of the cloned p65 subunit of NF-κB, a rel-related polypeptideCell, 1991
- Cloning of the p50 DNA binding subunit of NF-κB: Homology to rel and dorsalCell, 1990