Letters to Nature

Nature 423, 545-550 (29 May 2003) | ; Received 19 February 2003; Accepted 1 April 2003

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

Fumiaki Ohtake1, Ken-ichi Takeyama1,2, Takahiro Matsumoto1, Hirochika Kitagawa1, Yasuji Yamamoto3, Keiko Nohara4,5, Chiharu Tohyama4,5, Andree Krust6, Junsei Mimura5,7, Pierre Chambon6, Junn Yanagisawa1,2, Yoshiaki Fujii-Kuriyama5,7 & Shigeaki Kato1,2

  1. The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
  2. SORST, Japan Science and Technology, Kawaguchi, Saitama 332-0012, Japan
  3. Taiho Pharmaceutical Company Ltd, Cancer Research Laboratory, Hanno Research Center, Hanno, Saitama, 357-8527, Japan
  4. National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
  5. CREST, Japan Science and Technology, Kawaguchi, Saitama 332-0012, Japan
  6. Institut de Génétique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Collège de France, 67404 Illkirch, Strasbourg, France
  7. TARA Center, University of Tsukuba, Tennodai, Tsukuba, 305-8577, Japan

Correspondence to: Shigeaki Kato1,2 Correspondence and request s for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).

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-alpha and ER-beta. 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-alpha-/- 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.