Astapova Inna, Hollenberg Anthony N
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Biochim Biophys Acta. 2013 Jul;1830(7):3876-81. doi: 10.1016/j.bbagen.2012.07.001. Epub 2012 Jul 16.
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 T3in 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. This article is part of a Special Issue entitled Thyroid hormone signalling.
甲状腺激素受体（TR）亚型根据三碘甲状腺原氨酸（T3）的可利用性与多种共调节因子相互作用，以介导其转录效应。传统上，在没有配体的情况下，TR会募集核共抑制因子NCoR和SMRT，以介导对正向调节的TR靶基因的转录抑制。然而，利用体内模型对NCoR和SMRT作用的新见解，更好地明确了核共抑制因子在T3存在和不存在时的作用。
本综述将把迄今为止开发的各种体内核共抑制因子小鼠模型置于甲状腺激素作用的背景下进行讨论。基于这些模型，我们还将讨论共抑制因子的可利用性以及包括T3在内的内源性核受体配体水平如何控制多种信号通路。
在体内缺乏T3的情况下，核共抑制因子介导对正向TR靶标的抑制。更重要的是，它们在配体的正常生理水平下减弱TR和其他核受体对这些靶标的激活。虽然共抑制因子在负向TR靶标和下丘脑-垂体-甲状腺（HPT）轴调节中的作用仍知之甚少，但动物体内TR缺乏共抑制因子募集会导致HPT轴设定点的代偿性变化，从而平衡其他组织中对T3作用增加的敏感性。
现有数据表明，针对共抑制因子与TR或其他核受体之间的特定相互作用，为内分泌和代谢紊乱提供了一种新的治疗策略。本文是名为“甲状腺激素信号传导”的特刊的一部分。
