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

F Ohtake, K Takeyama, T Matsumoto, H Kitagawa… - Nature, 2003 - nature.com
F Ohtake, K Takeyama, T Matsumoto, H Kitagawa, Y Yamamoto, K Nohara, C Tohyama…
Nature, 2003nature.com
Environmental contaminants affect a wide variety of biological events in many species.
Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects.
Although their anti-oestrogenic actions, are well described, dioxins can also induce
endometriosis,,, and oestrogen-dependent tumours,, 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 …
Abstract
Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects. Although their anti-oestrogenic actions, are well described, dioxins can also induce endometriosis,,, and oestrogen-dependent tumours,, 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 dioxins,. 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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