Modulation of oestrogen receptor signalling by association with the activated dioxin receptor

Fumiaki Ohtake, Ken-ichi Takeyama, Takahiro Matsumoto, Hirochika Kitagawa, Yasuji Yamamoto, Keiko Nohara, Chiharu Tohyama, Andree Krust, Junsei Mimura, Pierre Chambon, Junn Yanagisawa, Yoshiaki Fujii-Kuriyama and Shigeaki Kato ()
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Fumiaki Ohtake: University of Tokyo
Ken-ichi Takeyama: University of Tokyo
Takahiro Matsumoto: University of Tokyo
Hirochika Kitagawa: University of Tokyo
Yasuji Yamamoto: Taiho Pharmaceutical Company Ltd, Cancer Research Laboratory, Hanno Research Center
Keiko Nohara: National Institute for Environmental Studies
Chiharu Tohyama: National Institute for Environmental Studies
Andree Krust: Institut de Génétique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Collège de France
Junsei Mimura: CREST, Japan Science and Technology
Pierre Chambon: Institut de Génétique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Collège de France
Junn Yanagisawa: University of Tokyo
Yoshiaki Fujii-Kuriyama: CREST, Japan Science and Technology
Shigeaki Kato: University of Tokyo

Nature, 2003, vol. 423, issue 6939, 545-550

Abstract: Abstract Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects1. Although their anti-oestrogenic actions2,3 are well described, dioxins can also induce endometriosis4,5,6,7 and oestrogen-dependent tumours8,9, implying possible oestrogenic effects. However, the molecular mechanism underlying oestrogen-related actions of dioxins remains largely unknown. A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix–loop–helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins10,11. Here we show that the agonist-activated AhR/Arnt heterodimer directly associates with oestrogen receptors ER-α and ER-β. This association results in the recruitment of unliganded ER and the co-activator p300 to oestrogen-responsive gene promoters, leading to activation of transcription and oestrogenic effects. The function of liganded ER is attenuated. Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-α-/- ovariectomized mice. Our findings suggest a novel mechanism by which ER-mediated oestrogen signalling is modulated by a co-regulatory-like function of activated AhR/Arnt, giving rise to adverse oestrogen-related actions of dioxin-type environmental contaminants.

Date: 2003
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DOI: 10.1038/nature01606

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