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


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.

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Figure 1: Activation of unliganded ER function by liganded dioxin receptor heterodimer.
Figure 2: 3MC-dependent interaction of ERs with AhR/Arnt.
Figure 3: 3MC-dependent recruitment of AhR/Arnt to ER-α bound on oestrogen-responsive gene promoters.
Figure 4: Oestrogenic actions of 3MC in mouse uterus are mediated by AhR and ER-α.

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We thank K. Korach and A. Fukamizu for helpful discussion; T. Sato, A. Murayama and Y. Kobayashi for technical assistance; Taiho Pharmaceutical Co. for ER ligands; and R. Nakamura and H. Higuchi for manuscript preparation. This work was supported in part by grants-in-aid for priority areas from the Ministry of Education, Science, Sports and Culture of Japan (to Y.F.-K. and S.K.).

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Correspondence to Shigeaki Kato.

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Ohtake, F., Takeyama, Ki., Matsumoto, T. et al. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423, 545–550 (2003).

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