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

Author

Listed:
  • Fumiaki Ohtake

    (University of Tokyo)

  • Ken-ichi Takeyama

    (University of Tokyo
    SORST, Japan Science and Technology)

  • 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
    CREST, Japan Science and Technology)

  • Chiharu Tohyama

    (National Institute for Environmental Studies
    CREST, Japan Science and Technology)

  • 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
    #TARA Center, University of Tsukuba)

  • Pierre Chambon

    (Institut de Génétique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Collège de France)

  • Junn Yanagisawa

    (University of Tokyo
    SORST, Japan Science and Technology)

  • Yoshiaki Fujii-Kuriyama

    (CREST, Japan Science and Technology
    #TARA Center, University of Tsukuba)

  • Shigeaki Kato

    (University of Tokyo
    SORST, Japan Science and Technology)

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.

Suggested Citation

  • Fumiaki Ohtake & Ken-ichi Takeyama & Takahiro Matsumoto & Hirochika Kitagawa & Yasuji Yamamoto & Keiko Nohara & Chiharu Tohyama & Andree Krust & Junsei Mimura & Pierre Chambon & Junn Yanagisawa & Yosh, 2003. "Modulation of oestrogen receptor signalling by association with the activated dioxin receptor," Nature, Nature, vol. 423(6939), pages 545-550, May.
  • Handle: RePEc:nat:nature:v:423:y:2003:i:6939:d:10.1038_nature01606
    DOI: 10.1038/nature01606
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    Cited by:

    1. Lucia Coppola & Sabrina Tait & Enrica Fabbrizi & Monia Perugini & Cinzia La Rocca, 2022. "Comparison of the Toxicological Effects of Pesticides in Non-Tumorigenic MCF-12A and Tumorigenic MCF-7 Human Breast Cells," IJERPH, MDPI, vol. 19(8), pages 1-18, April.

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