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The Transcription Factor Aryl Hydrocarbon Receptor Nuclear Translocator Functions as an Estrogen Receptor β-Selective Coactivator, and Its Recruitment to Alternative Pathways Mediates Antiestrogenic Effects of Dioxin

Karolinska Institute (J.R., E.S., D.W., K.P., I.P.), Department of Biosciences and Nutrition, S-141 57 Huddinge, Sweden; Karolinska Institute (D.W.), Institute of Environmental Medicine, S-171 77 Solna, Sweden; and Institut National de la Santé et de la Recherche Médicale Unité 824 (A.E., P.B.) Montpellier F-34298, France

Address all correspondence and requests for reprints to: Ingemar Pongratz, Karolinska Institute, Department of Biosciences and Nutrition, S-141 57 Huddinge, Sweden. E-mail: Ingemar.Pongratz{at}biosci.ki.se.

The biological effects of dioxins are mediated by the aryl hydrocarbon receptor (AhR) and its dimerization partner, the AhR nuclear translocator (ARNT), and include interference with hormonal signaling pathways like the response to estrogens. The effects of estrogens are mediated by two estrogen receptor (ER) isoforms, ER and ERβ, which belong to the family of nuclear receptors. We have previously shown that ARNT can act as coactivator of the ERs. In this study, we show that recruitment of ARNT to AhR or hypoxia-inducible factor-1 signaling pathways as well as small interfering RNA-mediated down-regulation of ARNT levels lead to a reduction in ER transcriptional activity. Using chromatin immunoprecipitation assays, we demonstrate that this decrease coincides with reduced recruitment of ARNT to estradiol-regulated promoters. We show further that coactivation by ARNT as well as inhibition by dioxin acts stronger on ERβ than on ER activity. Additionally, we demonstrate that the effects of ARNT are dependent on the A/B domain of the ERs with the A/B domain of ERβ being considerably stronger in mediating the coactivating effects of ARNT. Taken together, our studies show that recruitment of ARNT to the AhR after dioxin treatment can account for the antiestrogenic effect of dioxins. Moreover, we show for the first time that the inhibitory effects of dioxin are more pronounced on ERβ than on ER.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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