The in vivo role of nuclear receptor corepressors in thyroid hormone action.
The in vivo role of nuclear receptor corepressors in thyroid hormone action.
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DOI：
10.1016/j.bbagen.2012.07.001
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发表时间：
2013-07
影响因子：
3
通讯作者：
Hollenberg, Anthony N.
中科院分区：
文献类型：
--
作者：
Astapova, Inna;Hollenberg, Anthony N.
甲状腺激素受体 (TR) 亚型与多种辅助调节因子相互作用，具体取决于 T3 的可用性来介导其转录作用。传统上，在没有配体的情况下，TR 会招募核辅阻遏物 NCoR 和 SMRT，以介导正向调节的 TR 靶基因的转录抑制。然而，使用体内模型对 NCoR 和 SMRT 作用的新见解更好地定义了核辅阻遏物在 T3 不存在和存在的情况下的作用。本综述将把迄今为止开发的各种体内核辅阻遏物小鼠模型置于甲状腺激素作用的背景下。基于这些模型，我们还将讨论辅阻遏物的可用性以及内源性核受体配体（包括 T3）的水平如何控制多种信号通路。在体内缺乏 T3 的情况下，核辅阻遏物介导对阳性 TR 靶标的抑制。更重要的是，它们减弱了 TR 和其他核受体在配体正常生理水平上对这些靶标的激活。虽然辅阻遏物在负 TR 靶点和 HPT 轴调节中的作用仍知之甚少，但动物中缺乏向 TR 募集辅阻遏物会导致 HPT 轴设定点发生补偿性变化，从而平衡其他组织中对 T3 作用的敏感性增加。现有数据表明，针对辅阻遏物与 TR 或其他核受体之间的特异性相互作用，为内分泌和代谢紊乱提供了一种新的治疗策略。
The thyroid hormone receptor (TR) isoforms interact with a variety of coregulators depending upon the availability of T3 to mediate their transcriptional effect. Classically, in the absence of ligand, the TRs recruit the nuclear corepressors, NCoR and SMRT, to mediate transcriptional repression on positively regulated TR target genes. However, new insight into the roles of NCoR and SMRT using in vivo models have better defined the role of nuclear corepressors both in the absence and presence of T3. This review will place the variety of in vivo nuclear corepressor mouse models developed to date in context of thyroid hormone action. Based on these models, we will also discuss how corepressor availability together with the levels of endogenous nuclear receptor ligands including T3 controls multiple signaling pathways. Nuclear corepressors mediate repression of positive TR targets in the absence of T3 in vivo. Even more importantly they attenuate activation of these targets at the normal physiological levels of ligands by TR and other nuclear receptors. While the role of corepressors in the regulation of negative TR targets and HPT axis remains poorly understood, lack of corepressor recruitment to TR in the animals leads to a compensatory change in the set point of HPT axis that allows to balance the increased sensitivity to T3 action in other tissues. Available data indicate that targeting specific interactions between corepressors and TR or other nuclear receptors presents a new therapeutic strategy for endocrine and metabolic disorders.
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影响因子：
64.8
作者：
Alenghat, Theresa;Meyers, Katherine;Mullican, Shannon E.;Leitner, Kirstin;Adeniji-Adele, Adetoun;Avila, Jacqueline;Bucan, Maja;Ahima, Rexford S.;Kaestner, Klaus H.;Lazar, Mitchell A.
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Lazar, Mitchell A.
影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
Sutanto, Maria M.;Ferguson, Kelly K.;Cohen, Ronald N.
通讯作者：
Cohen, Ronald N.