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J. Biol. Chem., Vol. 282, Issue 15, 10881-10893, April 13, 2007

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A Novel Promoter Element Containing Multiple Overlapping Xenobiotic and Hypoxia Response Elements Mediates Induction of Cytochrome P4502S1 by Both Dioxin and Hypoxia^*

Steven P. Rivera¹², Feng Wang¹, Sirkku T. Saarikoski³, Robert T. Taylor^¶4, Brett Chapman, Ruixue Zhang, and Oliver Hankinson⁵

From the Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center and the ^¶Molecular Toxicology Interdepartmental Doctoral Program, UCLA, Los Angeles, California 90095 and the Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki FI-00250, Finland

Cytochrome P4502S1 (CYP2S1) is expressed at high levels in epithelial tissues and is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) via the aryl hydrocarbon receptor (AHR). Transcriptional initiation of mouse Cyp2s1 was found to occur at three regions, 198, 102, and 22 nucleotides from the translational initiation codon. Approximately 400 nucleotides upstream of its translational initiation codon, mouse Cyp2s1 contains three overlapping xenobiotic-responsive element (XRE) sequences, which make a major contribution toward dioxin inducibility. Each XRE sequence in this trimeric XRE can bind the AHR/aryl hydrocarbon receptor nuclear translocator (ARNT) dimer in a dioxin-dependent fashion in vitro and can mediate dioxin-dependent transcription. Cyp2s1 is also markedly inducible by hypoxia. Induction is dependent on hypoxiainducible factor-1 (HIF-1) and is mediated in large part by three overlapping hypoxia response elements (HREs) embedded within the trimeric XRE segment. Although each HRE within this segment can bind HIF-1/ARNT in vitro, the most 3' HRE contributes the most toward hypoxia inducibility. AHR/ARNT and HIF-1/ARNT dimers bind to the region containing the trimeric XRE segment of the endogenous Cyp2s1 gene in vivo in a dioxin-dependent fashion and hypoxia-dependent fashion, respectively. These observations identify a novel regulatory cassette that mediates changes in Cyp2s1 expression.

Received for publication, October 12, 2006 , and in revised form, February 2, 2007.

^* This work was supported by National Institutes of Health Grants R01 ES015384 and R01 CA028868. 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.

¹ These authors contributed equally to this work.

² Present address: Nichols Institute, Quest Diagnostics, 33608 Ortega Hwy., San Juan Capistrano, CA 92675.

³ Supported in part by Academy of Finland Grant 52276.

⁴ Supported in part by a fellowship from the University of California Toxic Substances Research and Teaching Program.

⁵ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, UCLA, 10833 Le Conte Ave, P.O. Box 951732, Los Angeles, CA 90095-1732. Tel.: 310-825-2936; Fax: 310-794-9272; E-mail: ohank{at}mednet.ucla.edu.

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