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J. Biol. Chem., Vol. 277, Issue 38, 35232-35239, September 20, 2002

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Role of AP-1 in the Coordinate Induction of Rat Glutamate-cysteine Ligase and Glutathione Synthetase by tert-Butylhydroquinone^*

Heping Yang, Ying Zeng, Taunia D. Lee^§, Yang Yang, Xiaopeng Ou, Lixin Chen, Masudul Haque, Richard Rippe^¶, and Shelly C. Lu

From the  Division of Gastroenterology and Liver Diseases, University of Southern California Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and the ^¶ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

GSH synthesis occurs via two enzymatic steps catalyzed by glutamate-cysteine ligase (GCL, made up of two subunits) and GSH synthetase (GS). Recently, we described coordinate induction of GCL subunits and GS. To study GS transcriptional regulation, we have cloned and characterized a 2.2-kb 5'-flanking region of the rat GS (GenBank^TM accession number AF333982). One transcriptional start site is located at 51 nucleotides upstream of the translational start site. The rat GS promoter drove efficiently luciferase expression in H4IIE cells. Sequential deletion analysis revealed DNA regions that are involved in positive and negative regulation. One repressor identified was NF1. tert-Butylhydroquinone (TBH) exerted a dose- and time-dependent increase in the mRNA level and promoter activity of both GCL subunits and GS. TBH increased protein binding to several regions of the GS promoter, c-jun expression, and activator protein 1 (AP-1) binding activity to several of the putative AP-1-binding sites of the GS promoter. Blocking AP-1 binding with dominant-negative c-jun led to decreased basal expression and significantly blocked the TBH-induced increase in promoter activity and mRNA level of all three genes. In conclusion, AP-1 is required for basal expression of GCL and GS; while NF1 serves as a repressor of GS, increased AP-1 transactivation is the predominant mechanism for coordinate induction of GCL and GS expression by TBH.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF333982.

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