Intrinsic AhR function underlies cross-talk of dioxins with sex hormone signalings
Intrinsic AhR function underlies cross-talk of dioxins with sex hormone signalings
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DOI：
10.1016/j.bbrc.2008.03.054
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发表时间：
2008-06-13
影响因子：
3.1
通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
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作者：
Ohtake, Fumiaki;Baba, Atsushi;Kato, Shigeaki
芳烃受体（AhR）介导性类固醇激素相关的行动在正常生理和二恶英毒性。除了直接靶基因的调节之外，配体激活的AhR与雌激素或雄激素受体（ER α或AR）结合以调节作为功能单元的转录。鉴于内源性和外源性AhR配体在结构上是不同的，目前还不清楚激活的AhR对ER α/AR的串扰调节是AhR的内在功能还是配体类型选择性差异的结果。为了确保AhR的均匀活性，而不管配体类型特异性差异如何，我们采用了CA-AhR，其缺乏配体结合结构域并且具有组成性活性。我们发现，CA-AhR，在没有配体的情况下，作为一个转录辅助调节器的unliganded ER α/AR以及ER α/AR的突变体缺乏配体结合域。CA-AhR被募集到雌激素/雄激素应答启动子与内源性激素ER α/AR。此外，CA-AhR具有E3泛素连接酶活性，并促进ER α/AR的蛋白酶体降解。因此，这些发现表明AhR与性激素受体的串扰功能是AhR的内在功能。(c)2008年爱思唯尔公司All rights reserved.
The arylhydrocarbon receptor (AhR) mediates sex steroid hormone-related actions in both normal physiology and in dioxin toxicity. In addition to regulation of direct target genes, the ligand-activated AhR associates with estrogen or androgen receptors (ER alpha or AR) to regulate transcription as a functional unit. Given that endogenous and exogenous AhR-ligands are structurally diverse, it is unclear whether crosstalk regulation of ER alpha/AR by the activated AhR is an intrinsic function of the AhR or the result of ligand-type-selective differences. To ensure uniform activity of the AhR irrespective of ligand-type-specific differences, we employed CA-AhR, which lacks the ligand-binding domain and has a constitutive activity. We found that CA-AhR, in the absence of a ligand, acted as a transcriptional co-regulator for the unliganded ER alpha/AR as well as for mutants of ER alpha/AR lacking a ligand-binding domain. CA-AhR was recruited to estrogen-/androgen-responsive promoters with endogencrus ER alpha/AR. Moreover, CA-AhR had an E3 ubiquitin ligase activity and promoted proteasomal degradation of ER alpha/AR. Thus, these findings indicate that the cross-talk function of the AhR with sex hormone receptors is an intrinsic function of the AhR. (c) 2008 Elsevier Inc. All rights reserved.