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J. Biol. Chem., Vol. 279, Issue 48, 49842-49848, November 26, 2004
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¶
From the
Department of Pathology and
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089
The aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are DNA binding transcription factors with basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) domains. These two proteins form a heterodimer that mediates the toxic and biological effects of the environmental contaminant and AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. The coiled-coil protein coiled-coil coactivator (Co-CoA) is a secondary coactivator for nuclear receptors and enhances nuclear receptor function by interacting with the bHLH-PAS domain of p160 coactivators. We report here that CoCoA also binds the bHLH-PAS domains of AHR and ARNT and functions as a potent primary coactivator for them; i.e. CoCoA does not require p160 coactivators for binding to and serving as a coactivator for AHR and ARNT. Endogenous CoCoA was recruited to a natural AHR target gene promoter in a 2,3,7,8-tetrachlorodibenzo-p-dioxin -dependent manner. Moreover, reduction of CoCoA mRNA levels by small interfering RNA inhibited the transcriptional activation by AHR and ARNT. Our data support a physiological role for CoCoA as a transcriptional coactivator in AHR/ARNT-mediated transcription.
Received for publication, July 28, 2004 , and in revised form, September 20, 2004.
* This work was supported in part by National Institutes of Health Grant DK43093 (to M. R. S.). 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 by a predoctoral fellowship from the University of Southern California/Norris Breast Cancer Research Training Program. To whom correspondence should be addressed: Dept. of Pathology, HMR 301, University of Southern California, 2011 Zonal Ave., Los Angeles, CA 90089-9092. Tel.: 323-442-1289; Fax: 323-442-3049; E-mail: stallcup{at}usc.edu.
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