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
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
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DOI：
10.1210/me.2007-0128
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发表时间：
2008-02-01
影响因子：
--
通讯作者：
Pongratz, Ingemar
中科院分区：
文献类型：
--
作者：
Rueegg, Joeelle;Swedenborg, Elin;Pongratz, Ingemar
二恶英的生物学效应是由芳烃受体（AhR）及其二聚化伙伴AhR核转运子（ARNT）介导的，包括干扰激素信号通路，如对雌激素的反应。雌激素的作用是由两种雌激素受体（ER）异构体，ER α和ER β介导的，它们属于核受体家族。我们之前已经表明，ARNT可以作为er的辅激活剂。在这项研究中，我们发现ARNT被募集到AhR或缺氧诱导因子-1 α信号通路，以及小干扰rna介导的ARNT水平下调导致内质网转录活性降低。使用染色质免疫沉淀试验，我们证明这种减少与雌二醇调节启动子的ARNT募集减少相一致。我们进一步表明，ARNT的共激活以及二恶英的抑制作用对ER β的作用强于ER α活性。此外，我们证明了ARNT的作用依赖于内质网的A/B结构域，而内质网β的A/B结构域在介导ARNT的共激活作用方面要强得多。综上所述，我们的研究表明，二恶英治疗后，ARNT向AhR募集可以解释二恶英的抗雌激素作用。此外，我们首次表明二恶英对ER β的抑制作用比ER α更明显。
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 alpha and ER beta, 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 alpha 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 ER beta than on ER alpha 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 ER beta 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 ER beta than on ER alpha.