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

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-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.

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

“…302 A more recent study showed no effect of E2 on 3-methylcholanthrene-inducible AhR activity, but failed to investigate the effects of E2 on HAH-mediated AhRC activity. 229 We have demonstrated that estradiol-activated ERα directly represses AhRC activity at the transcriptional level via tethering to the AhRC in MCF-7 cells. 226 However, others have reported the E2-inducible enhancement of TCDD-dependent CYP1A1 expression in T47D human breast cancer and Huh7 liver cell lines, while having little or no effect in MCF-7 cells.…”

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

“…The protein composition of these complexes determines the overall transcriptional effect exerted by the receptor (Yanagisawa et al, 2002;Kitagawa et al, 2003;Ohtake et al, 2003). Interaction of retinoid receptors with b-catenin at the Id2 gene WRE presumably leads to recruitment of repressor complexes containing histone deacetylase and demethylase activities.…”

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

“…Higher concentrations of up to 25 mM CH-223191 did not provide a stronger inhibition of pT81/3 Â DRE reporter activity (data not shown). Further, the cells were exposed to 3-MC, which induces DRE reporter activity at this concentration in other models (Ohtake et al, 2003). The pT81/3 Â DRE reporter was inducible by 3-MC in all glioma cell lines tested, as well as in the human astrocytic cell line.…”