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J. Biol. Chem., Vol. 279, Issue 52, 54620-54628, December 24, 2004

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Recruitment of Thyroid Hormone Receptor/Retinoblastoma-interacting Protein 230 by the Aryl Hydrocarbon Receptor Nuclear Translocator Is Required for the Transcriptional Response to Both Dioxin and Hypoxia^*

Timothy V. Beischlag¶, Robert T. Taylor||, David W. Rose**, Diana Yoon, Yumay Chen, Wen-Hwa Lee, Michael G. Rosenfeld, and Oliver Hankinson¶¶

From the Department of Pathology and Laboratory Medicine, Molecular Biology Institute, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California, 90095, the Howard Hughes Medical Institute, Department of Molecular Medicine, and the ^**Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, the Department of Medicine, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, and the Department of Biological Chemistry, University of California, Irvine, California 92697

The aryl hydrocarbon receptor nuclear translocator/hypoxia-inducible factor (ARNT/HIF-1) mediates an organism's response to various environmental cues, including those to chemical carcinogens, such as 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD or dioxin), via its formation of a functional transcription factor with the ligand activated aryl hydrocarbon receptor (AHR). Similarly, tissue responses to hypoxia are largely mediated through the HIF-1 heterodimeric transcription factor, comprising hypoxia-inducible factor-1 (HIF-1) and ARNT. The latter response is essential for a metabolic switch from oxidative phosphorylation to glycolytic anaerobic metabolism as well as for angiogenesis and has been implicated as necessary for growth in many solid tumors. In this report, we demonstrate that the thyroid hormone receptor/retinoblastoma-interacting protein 230 (TRIP230) interacts directly with ARNT and is essential for both hypoxic and TCDD-mediated transcriptional responses. We initially identified TRIP230 as an ARNT-interacting protein in a yeast two-hybrid assay screen. This interaction was confirmed in mammalian cell systems using co-immunoprecipitation and in mammalian two-hybrid assays. Furthermore, TRIP230 could be recorded at sites of activated transcription of either TCDD- or hypoxia-inducible genes in a stimulus-dependent fashion by chromatin immunoprecipitation analysis. Finally, using single-cell microinjection and RNA interference assays, we demonstrate that TRIP230 is indispensable for TCDD- and hypoxia-dependent gene transcription.

Received for publication, September 10, 2004 , and in revised form, October 8, 2004.

^* This work was supported by NCI, National Institutes of Health, Grant CA28868. 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.

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

^|| Supported by Research Supplement to Underrepresented Minorities to CA28868.

^¶¶ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, UCLA Medical Center, Center for Health Sciences, 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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