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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