Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone
Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone
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DOI：
10.1128/mcb.17.5.2642
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发表时间：
1997-05-01
影响因子：
5.3
通讯作者：
Jameson, JL
中科院分区：
文献类型：
--
作者：
Tagami, T;Madison, LD;Jameson, JL
一组转录辅因子被称为辅阻遏物（CoRs），最近被证明在含有阳性三碘甲状腺原氨酸（T3）反应元件的基因的基础沉默中起核心作用。以相互的方式，负调控的基因被未配体的甲状腺激素受体（TR）刺激，并在加入T3时被阻遏。它不能与CoRs相互作用，以检查CoRs是否也在响应T3的负调控基因的控制中发挥作用，在三个负调控基因的研究中，（垂体促甲状腺激素α亚单位[TSH α]、TSH β和下丘脑促甲状腺激素释放激素[TRH]基因），通过引入P214 R CoR突变，未配体TR β对基础启动子活性的刺激被削弱，每个CoR SMRT的共表达，（类维生素A受体和TR的沉默介质）和NCoR（核受体CoR）以TR依赖性方式增强负调控启动子的基础刺激，但在P214 R TR突变体中没有观察到这种效应。用一系列GAL 4-TR嵌合受体和突变体进一步探索了CoR对负调节启动子的作用机制，所述嵌合受体和突变体允许独立于受体与DNA的相互作用来评估TR作用。这些实验表明，与野生型TR对基因的负调节一样，GAL 4-TR发生基础激活，但GAL 4-P214 R突变体不发生基础激活。这些结果表明，TR与负调控基因的相互作用可能是通过蛋白质-蛋白质相互作用驱动的。我们得出结论，一个亚组的负调控基因是由一种新的机制，涉及TR介导的募集和基础激活SMRT和NCoR。添加T3逆转基础激活，可能是通过解离的CoRs。
A group of transcriptional cofactors referred to as corepressors (CoRs) were recently shown to play a central role in basal silencing of genes that contain positive triiodothyronine (T3) response elements, In a reciprocal manner, negatively regulated genes are stimulated by unliganded thyroid hormone receptor (TR) and repressed upon the addition of T3, We used a TR beta mutant, called P214R, which fails to interact with CoRs, to examine whether CoRs also play a role in the control of genes that are negatively regulated in response to T3, In studies of three negatively regulated genes (the pituitary thyroid-stimulating hormone alpha-subunit [TSH alpha], TSH beta, and hypothalamic thyrotropin-releasing hormone [TRH] genes), stimulation of basal promoter activity by unliganded TR beta was impaired by introducing the P214R CoR mutation, Coexpression of each of the CoRs SMRT (silencing mediator for retinoid receptors and TRs) and NCoR (nuclear receptor CoR) enhanced basal stimulation of the negatively regulated promoters in a TR-dependent manner, but this effect was not seen with the P214R TR mutant. The mechanism of CoR effects on negatively regulated promoters was explored further with a series of GAL4-TR chimeric receptors and mutants that allowed TR effects to be assessed independently of receptor interactions with DNA, These experiments revealed that, like the negative regulation of genes by wild-type TR, basal activation occurred with GAL4-TR, but not with the GAL4-P214R mutant, and was reversed by the addition of T3, These results suggest that TR interactions with negatively regulated genes may be driven through protein-protein interactions, We conclude that a subset of negatively regulated genes are controlled by a novel mechanism that involves TR-mediated recruitment and basal activation by SMRT and NCoR. Addition of T3 reverses basal activation, perhaps by dissociation of CoRs.