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

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 22; no. 2; pp. 304 - 316
• Main Authors: Rüegg, Joëlle, Swedenborg, Elin, Wahlström, David, Escande, Aurelie, Balaguer, Patrick, Pettersson, Katarina, Pongratz, Ingemar
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-02-2008; Oxford University Press
• Subjects: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Cell Hypoxia; Cell Line; Cell Line, Tumor; Chromatin Immunoprecipitation; Dimerization; Dioxins - pharmacology; Estradiol - pharmacology; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - chemistry; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medicin och hälsovetenskap; Models, Biological; Mutation; Polychlorinated Dibenzodioxins - pharmacology; Promoter Regions, Genetic - genetics; Protein Binding; Protein Structure, Tertiary; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction - drug effects; Transcription, Genetic - drug effects
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2007-0128

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, ERα 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-1α 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 ERα 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 ERα.