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Originally published In Press as doi:10.1074/jbc.M105607200 on September 10, 2001

J. Biol. Chem., Vol. 276, Issue 45, 41841-41849, November 9, 2001
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Definition of a Dioxin Receptor Mutant That Is a Constitutive Activator of Transcription
DELINEATION OF OVERLAPPING REPRESSION AND LIGAND BINDING FUNCTIONS WITHIN THE PAS DOMAIN*

Jacqueline McGuireDagger , Kensaku OkamotoDagger , Murray L. Whitelaw§, Hirotoshi Tanaka, and Lorenz PoellingerDagger ||

From the Dagger  Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden, the § Department of Biochemistry, University of Adelaide, Adelaide, South Australia 5005, Australia, and the  Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

The intracellular dioxin (aryl hydrocarbon) receptor is a ligand-activated transcription factor that mediates the adaptive and toxic responses to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and structurally related congeners. Whereas the ligand-free receptor is characterized by its association with the molecular chaperone hsp90, exposure to ligand initiates a multistep activation process involving nuclear translocation, dissociation from the hsp90 complex, and dimerization with its partner protein Arnt. In this study, we have characterized a dioxin receptor deletion mutant lacking the minimal ligand-binding domain of the receptor. This mutant did not bind ligand and localized constitutively to the nucleus. However, this protein was functionally inert since it failed to dimerize with Arnt and to bind DNA. In contrast, a dioxin receptor deletion mutant lacking the minimal PAS B motif but maintaining the N-terminal half of the ligand-binding domain showed constitutive dimerization with Arnt, bound DNA, and activated transcription in a ligand-independent manner. Interestingly, this mutant showed a more potent functional activity than the dioxin-activated wild-type receptor in several different cell lines. In conclusion, the constitutively active dioxin receptor may provide an important mechanistic tool to investigate receptor-mediated regulatory pathways in closer detail.

* This work was supported by grants from the Swedish Cancer Society, the European Union, and the NOVARTIS Foundation (Japan) for the Promotion of Science.The costs of publication of this article were defrayed in part by the payment of page charges. The 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. Tel.: 46-8-728-7330; Fax: 46-8-34-88-19; E-mail: lorenz.poellinger@cmb.ki.se.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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