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J. Biol. Chem., Vol. 280, Issue 21, 20340-20348, May 27, 2005

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Transcriptional Regulation of NF-E2 p45-related Factor (NRF2) Expression by the Aryl Hydrocarbon Receptor-Xenobiotic Response Element Signaling Pathway

DIRECT CROSS-TALK BETWEEN PHASE I AND II DRUG-METABOLIZING ENZYMES^*

Weimin Miao, Lianggao Hu, P. James Scrivens, and Gerald Batist

From the Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis-Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec H3T 1E2, Canada

The aryl hydrocarbon receptor (AHR) and NF-E2 p45-related factor (NRF2) are two distinct transcription factors involved in the regulation of drug-metabolizing enzymes. Increasing evidence from several studies implies that AHR and NRF2 have direct links, but the molecular mechanism remains unknown. In this work we demonstrate for the first time that Nrf2 gene transcription is directly modulated by AHR activation. DNA sequence analyses of the mouse Nrf2 promoter revealed one xenobiotic response element (XRE)-like element (XREL1) located at –712 and two additional XRE-like elements located at +755 (XREL2) and +850 (XREL3). Functional analysis using luciferase assay showed that XREL1, XREL2, and XREL3 are all inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment, with XREL2 being the most potent. The functionality of these XRE-like elements was further confirmed by mutagenesis and gel shift experiments. Finally, we used chromatin immunoprecipitation assay to show a direct binding of AHR to the Nrf2 promoter. Cells with silenced AHR expression using siRNA also lost NRF2 mRNA induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin. These new data position NRF2-antioxidant response element downstream in the AHR-XRE pathway. Moreover, direct regulation of NRF2 by AHR contributes to couple phase I and II enzymes into an integrated system facilitating more effective xenobiotic and carcinogen detoxification.

Received for publication, October 25, 2004 , and in revised form, March 2, 2005.

^* This work was supported by grants from the Canadian Institutes for Health Research, Valorization Recherche Quebec, and the Fonds de la Recherche en Sante du Quebec. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Cote Sainte Catherine Rd., Montreal, Quebec H3T 1E2, Canada. Tel.: 514-735-1420; Fax: 514-735-7211; E-mail: gbatist{at}onc.jgh.mcgill.ca.

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