Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism
Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism
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DOI：
10.1074/jbc.m310531200
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发表时间：
2004-04-30
影响因子：
4.8
通讯作者：
Koibuchi, N
中科院分区：
文献类型：
--
作者：
Miyazaki, W;Iwasaki, T;Koibuchi, N
多氯联苯是一种破坏内分泌系统的环境化合物，暴露于低剂量会导致异常，特别是在发育中的中枢神经系统。因为它们在结构上类似于甲状腺激素(TH)，所以多氯联苯可能会影响涉及这种激素的系统。我们先前使用报告分析发现，低至10(-10)M剂量的羟化多氯联苯抑制TH诱导的TH受体(TR)的转录激活。为了了解这一过程的分子机制，我们研究了多氯联苯是否改变了辅活化子或辅抑制子与TR的相互作用。在哺乳动物双杂交和谷胱甘肽S转移酶下拉研究中，多氯联苯抑制类固醇受体辅活化子-1促进转录，但不减少类固醇受体辅活化子-1的相互作用。因此，这种抑制很可能不是由辅激活子解离引起的。无论是在体内还是体外，核受体辅阻遏子都不能被多氯联苯募集到受体受体上，这表明核受体辅阻遏子结合不会诱导抑制。然后，我们检查了多氯联苯是否影响甲状腺激素反应元件(TRE)与TRR的结合。电泳迁移率改变分析表明，在多氯联苯存在下，TRR/维甲酸X受体异二聚体复合体与TrE部分解离。这些结果表明，TRR/维甲酸X受体异二聚体从TrE上的部分解离参与了多氯联苯诱导的转录抑制。
Polychlorinated biphenyls (PCBs) are environmental compounds that disrupt the endocrine system, and exposure to low doses causes abnormalities, particularly in the developing central nervous system. Because they are structurally similar to thyroid hormone (TH), PCBs might affect systems involving this hormone. We previously found, using reporter assays, that hydroxylated-PCB at doses as low as 10(-10) M suppress TH-induced transcriptional activation of TH receptor (TR). To understand the molecular mechanisms of this process, we examined whether PCBs alter coactivator or corepressor interaction with TR. Polychlorinated biphenyls suppressed steroid receptor coactivator-1 enhanced TR-mediated transcription, but did not reduce TR/steroid receptor coactivator-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. Thus, the suppression was probably not caused by coactivator dissociation. Nuclear receptor co-repressor was not recruited to TR by PCBs either in vivo or in vitro, indicating that TR corepressor binding did not induce the suppression. We then examined whether PCB influences TR binding to the thyroid hormone-response element (TRE). Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB. These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB.