Baniahmad A, Tsai S Y, O'Malley B W, Tsai M J
Baylor College of Medicine, Department of Cell Biology, Houston, TX 77030.
Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10633-7. doi: 10.1073/pnas.89.22.10633.
Mutations in the gene encoding the human thyroid hormone receptor beta (hTR beta) 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 (hTR delta 332) 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.
编码人类甲状腺激素受体β（hTRβ）的基因突变与全身性甲状腺激素抵抗（GTHR）有关。然而，受体突变体导致临床症状的分子基础在很大程度上尚不清楚。我们在此表明，人类受体的β形式除了具有激素依赖性激活能力外，还具有抑制靶启动子基础水平活性的能力。这种沉默功能定位于受体的羧基末端部分，并且可以转移到异源DNA结合结构域。因此，这种沉默模式不同于通过与DNA上的激活蛋白竞争来进行抑制。我们表明，从GTHR患者中分离出的两个受体突变体在转录激活方面受损，但完全保留了沉默功能，这增强了受体的显性负调控。有趣的是，亲属S受体（hTRδ332）作为一种组成型阻遏物，具有与v-erbA癌基因产物相似的强大沉默能力。我们还提供了这两种蛋白质不同转录调控特性的证据。最后，我们表明甲状腺激素和视黄酸反应性基因都可能被抑制，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重要作用。
