Molecular and Cellular Biology, July 2005, p. 5933-5946, Vol. 25, No. 14
0270-7306/05/$08.00+0 doi:10.1128/MCB.25.14.5933-5946.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Nrf1 and Nrf2 Regulate Rat Glutamate-Cysteine Ligase Catalytic Subunit Transcription Indirectly via NF-
B and AP-1
Heping Yang,1
Nathaniel Magilnick,1
Candy Lee,2
Denise Kalmaz,1
Xiaopeng Ou,1
Jefferson Y. Chan,2 and
Shelly C. Lu1*
Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, California 90033,1
Department of Pathology, University of California, Irvine, Irvine, California 926972
Received 20 August 2004/
Returned for modification 4 November 2004/
Accepted 12 April 2005
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-
B 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-
B 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-
B family members.
* Corresponding author. Mailing address: Division of Gastrointestinal and Liver Diseases, HMR Bldg., 415, Department of Medicine, Keck School of Medicine USC, 2011 Zonal Ave., Los Angeles, CA 90033. Phone: (323) 442-2441. Fax: (323) 442-3234. E-mail: shellylu{at}usc.edu.
Molecular and Cellular Biology, July 2005, p. 5933-5946, Vol. 25, No. 14
0022-538X/05/$08.00+0 doi:10.1128/MCB.25.14.5933-5946.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
This article has been cited by other articles:
-
Kode, A., Rajendrasozhan, S., Caito, S., Yang, S.-R., Megson, I. L., Rahman, I.
(2008). Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
294: L478-L488
[Abstract]
[Full Text]
-
Xing, W., Singgih, A., Kapoor, A., Alarcon, C. M., Baylink, D. J., Mohan, S.
(2007). Nuclear Factor-E2-related Factor-1 Mediates Ascorbic Acid Induction of Osterix Expression via Interaction with Antioxidant-Responsive Element in Bone Cells. J. Biol. Chem.
282: 22052-22061
[Abstract]
[Full Text]
-
Aleksunes, L. M., Manautou, J. E.
(2007). Invited Review: Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease. Toxicol Pathol
35: 459-473
[Abstract]
-
Minsavage, G. D., Dillman, J. F. III
(2007). Bifunctional Alkylating Agent-Induced p53 and Nonclassical Nuclear Factor {kappa}B Responses and Cell Death Are Altered by Caffeic Acid Phenethyl Ester: A Potential Role for Antioxidant/Electrophilic Response-Element Signaling. J. Pharmacol. Exp. Ther.
321: 202-212
[Abstract]
[Full Text]
-
Hock, T. D., Liby, K., Wright, M. M., McConnell, S., Schorpp-Kistner, M., Ryan, T. M., Agarwal, A.
(2007). JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells. J. Biol. Chem.
282: 6875-6886
[Abstract]
[Full Text]
Copyright © 2005 by the American Society for Microbiology. All rights reserved.