KINDRED S-THYROID HORMONE RECEPTOR IS AN ACTIVE AND CONSTITUTIVE SILENCER AND A REPRESSOR FOR THYROID-HORMONE AND RETINOIC ACID RESPONSES
KINDRED S-THYROID HORMONE RECEPTOR IS AN ACTIVE AND CONSTITUTIVE SILENCER AND A REPRESSOR FOR THYROID-HORMONE AND RETINOIC ACID RESPONSES
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DOI：
10.1073/pnas.89.22.10633
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发表时间：
1992-11-15
影响因子：
11.1
通讯作者：
TSAI, MJ
中科院分区：
文献类型：
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作者：
BANIAHMAD, A;TSAI, SY;TSAI, MJ
编码人类甲状腺激素受体β（hTRbeta）的基因突变与广义甲状腺激素抵抗（GTHR）有关。然而，受体突变体引起临床症状的分子基础在很大程度上尚不清楚。我们在这里表明，除了激素依赖性激活之外，人类受体的β形式还具有抑制靶启动子基础水平活性的能力。这种沉默功能位于受体的羧基末端部分，并且可以转移到异源 DNA 结合域。因此，这种沉默模式不同于通过与 DNA 上的激活蛋白竞争而产生的抑制。我们发现从 GTHR 患者中分离出的两种受体突变体的转录激活受到损害，但完全保留了沉默功能，从而增强了受体的显性负调节。有趣的是，同源S受体（hTRDELTA332）作为一种组成型阻遏蛋白，具有与v-erbA癌基因产物相似的强大沉默能力。我们还提供了两种蛋白质不同转录调控特性的证据。最后，我们发现甲状腺激素和视黄酸反应基因都可能受到抑制，从而产生 GTHR 综合征的临床表现。我们的研究结果表明沉默在 GTHR 患者症状的表型表达中起着重要作用。
Mutations in the gene encoding the human thyroid hormone receptor beta (hTRbeta) have been associated with generalized thyroid hormone resistance (GTHR). However, the molecular basis by which the receptor mutants cause the clinical symptoms is largely unknown. We show here that the beta form of the human receptor possesses, in addition to hormone-dependent activation, the ability to repress basal-level activity of a target promoter. This silencing function is localized in the carboxyl-terminal part of the receptor and can be transferred to a heterologous DNA binding domain. This mode of silencing is therefore distinct from inhibition by competition with activator proteins on DNA. We show that two receptor mutants isolated from patients with GTHR are impaired in transcriptional activation but fully retain the silencing function, which enforces dominant negative regulation by the receptor. Interestingly, the kindred S receptor (hTRDELTA332) acts as a constitutive repressor with a strong silencing ability similar to that of the v-erbA oncogene product. We also provide evidence for distinct transcriptional regulatory properties of both proteins. Finally, we show that both thyroid hormone- and retinoic acid-responsive genes are potentially repressed to generate the clinical manifestations of the GTHR syndrome. Our findings suggest that silencing plays an important role in the phenotypic expression of the symptoms in patients with GTHR.