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Department of Life Science (E.C.), Pohang University of Science and Technology, Pohang 790-784, Korea; Department of Molecular and Cellular Biology (S.L.), Division Diabetes, Endocrinology & Metabolism (J.W.L.), Department of Medicine, Baylor College of Medicine, Houston, Texas 77030; and Asan Institute for Life Sciences (S.-Y.Y., G.H.K., S.-W.K.), University of Ulsan College of Medicine, Seoul 138-736, Korea
Address all correspondence and requests for reprints to: Jae Woon Lee, Ph.D., Division Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030. E-mail: jwlee{at}bcm.tmc.edu; or Seung-Whan Kim, Ph.D., Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea. E-mail: swkim7{at}amc.seoul.kr.
Activating signal cointegrator-2 (ASC-2) is a recently isolated transcriptional coactivator protein for a variety of different transcription factors, including many members of the nuclear receptor superfamily. In this report, we demonstrate that ASC-2 also serves as a coactivator of the xenobiotic nuclear receptor constitutive androstane receptor (CAR). First, transcriptional activation by CAR was enhanced by cotransfected ASC-2 in CV-1 and HeLa cells. In contrast, CAR transactivation was significantly impaired in HepG2 cells stably expressing specific small interfering RNA directed against ASC-2. Consistent with these results, chromatin immunoprecipitation experiments revealed that ASC-2 is recruited to the known CAR target genes in a ligand-dependent manner. Secondly, CAR specifically interacted with the first LXXLL motif of ASC-2, and these interactions were stimulated by CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene and repressed by CAR inverse agonist androstanol, suggesting that this motif may mediate the interactions of ASC-2 and CAR in vivo. In support of this idea, DN1, a fragment of ASC-2 encompassing the first LXXLL motif, suppressed CAR transactivation, and coexpressed ASC-2 but not other LXXLL-type coactivators such as thyroid hormone receptor-associated protein 220 reversed this repression. Finally, CAR was recently found to play a pivotal role in effecting the severe acetaminophen-induced liver damage. Interestingly, transgenic mice expressing DN1 were resistant to the acetaminophen-induced hepatotoxicity and expression of a series of the known CAR target genes was specifically repressed in these transgenic mice. Taken together, these results strongly suggest that ASC-2 is a bona fide coactivator of the xenobiotic nuclear receptor CAR and mediate the specific xenobiotic response by CAR in vivo.
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