Cohen R N, Putney A, Wondisford F E, Hollenberg A N
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2000 Jun;14(6):900-14. doi: 10.1210/mend.14.6.0474.
The thyroid hormone receptor (TR) and retinoic acid receptor (RAR) isoforms have the capacity to silence gene expression in the absence of their ligands on target response elements. This active repression is mediated by the ability of the corepressors, nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), to recruit a complex containing histone deacetylase activity. Interestingly, NCoR and SMRT share significant differences in the their two nuclear receptor-interacting domains (IDs), suggesting that they may recruit receptors with different affinities. In addition, the role of the receptor complex bound to a response element has not been fully evaluated in its ability to recruit separate corepressors. We demonstrate in this report that the proximal ID in NCoR and SMRT, which share only 23% homology, allows preferential recognition of nuclear receptors, such that TR prefers to recruit NCoR, and RAR prefers to recruit SMRT, to DNA response elements. However, mutations in the TR found in the syndromes of resistance to thyroid hormone can change the corepressor recruited by changing the complex (homodimer or heterodimer) formed on the TRE. These results demonstrate that the corepressor complex recruited can be both nuclear receptor- and receptor complex-specific.
甲状腺激素受体（TR）和视黄酸受体（RAR）亚型在缺乏配体时，能够在靶反应元件上使基因表达沉默。这种主动抑制是由共抑制因子——核受体共抑制因子（NCoR）和视黄酸及甲状腺激素受体沉默介质（SMRT）——募集含有组蛋白去乙酰化酶活性的复合物的能力介导的。有趣的是，NCoR和SMRT在其两个核受体相互作用结构域（ID）上存在显著差异，这表明它们可能以不同亲和力募集受体。此外，与反应元件结合的受体复合物在募集不同共抑制因子的能力方面尚未得到充分评估。我们在本报告中证明，NCoR和SMRT中仅具有23%同源性的近端ID能够优先识别核受体，使得TR倾向于募集NCoR，而RAR倾向于募集SMRT至DNA反应元件。然而，在甲状腺激素抵抗综合征中发现的TR突变可通过改变在甲状腺激素反应元件（TRE）上形成的复合物（同二聚体或异二聚体）来改变所募集的共抑制因子。这些结果表明，所募集的共抑制因子复合物既可以是核受体特异性的，也可以是受体复合物特异性的。
