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FUNCTION OF COFACTORS MODIFYING THYROID HORMONE RECEPTOR FUNCTION

辅助因子改变甲状腺激素受体功能的功能

基本信息

批准号：
10470226
负责人：
SEO Hisao
金额：
$ 3.78万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470226/
关键词：
thyroid hormone receptor cofactor dominant negative action corepressor coactivator RXRα NF-κB

项目摘要

1. DETERMINATION OF CHROMOSOME LOCUS OF HUMAN NUCLEAR COREPRESSOR (hN-CoR)hN-CoR has been shown to associate with unliganded thyroid hormone receptor and to inhibits the transcription of target genes for thyroid hormone. We localized the locus of hN-CoR on chromosome 17q11.2 by FISH (fluorescent in situ hybridization) and Southern blot analysis using the panel of human and mouse hybrid cell lines. This was the first report on the localization of hN-CoR.2. STUDIES ON THE ROLE OF N-CoR IN THE PATHOGENESIS OF RESISTANCE TO THYROID HORMONE (RTH)RTH in most cases is inherited in an autosomal dominant manner. In most of the patients, point mutation were identified in the thyroid hormone receptor (TR) beta gene coding the ligand binding domain. It has been thus speculated that dominant negative action of mutant (TR) on normal TR is the key mechanism for the pathogenesis of RTH.A fact that more than 60 mutations were identified to date, no mutation was reported in the region coding the domain … More which interact with N-CoR.We thus studied whether the disruption of N-CoR binding site in a mutant TR abrogates the dominant negative action of the mutant receptor. It was demonstrated that the disruption eliminates the dominant negative action of the mutant receptor. It is suggested that binding of mutant TR with N-CoR is required for the dominant negative action of the mutant receptors.3. INTRACELLULAR DEGRADATION OF RETINOID X RECEPTOR (RXR)It is now accepted that TR exerts its action by heterodimer formation with RXR.It is thus speculated that the metabolism of RXR could modify the action of TR.We demonstrated that RXR is rapidly degraded by a cathepsin-L type protease, a lysozomal enzyme. Furthermore, it was demonstrated that inhibition of this enzyme resulted in an augmented response to thyroid hormone in hepatocyte, demonstrating the metabolism of RXR could influence the action of thyroid hormone.4. REGULAIION OF RXRa EXPRESSION BY GLUCOCORTICOID IN HEPATOCYTEMajor RXR expressed in the liver has been shown to be RXRα. We demonstrated that glucocorticoid increases the expression of RXRα and enhances thyroid hormone action, suggesting the cross talk between glucocorticoid and thyroid hormone.5. MODIFICATION OF THYROID HORMONE ACTION BY TNFαIt was demonstrated that nuclear factor kappa-B (NF-κB) activated by inhibits the thyroid hormone dependent activation of 5'-deiodinase gene in liver. This study suggested that mechanism involved in the development of euthyroid sick syndrome caused by an increase in TNFα could be NF-κB dependent inhibition of thyroid hormone action in liver. Less

1.人核辅阻遏物(hN-CoR)染色体位点的测定hN-CoR已被证明与未配体的甲状腺激素受体相关并抑制甲状腺激素靶基因的转录。我们使用人类和小鼠杂交细胞系组，通过 FISH（荧光原位杂交）和 Southern 印迹分析将 hN-CoR 基因座定位在染色体 17q11.2 上。这是关于 hN-CoR.2 定位的第一份报告。 N-CoR 在甲状腺激素 (RTH) 抵抗发病机制中的作用研究 RTH 在大多数情况下以常染色体显性方式遗传。在大多数患者中，在编码配体结合域的甲状腺激素受体（TR）β基因中发现了点突变。因此推测突变体（TR）对正常TR的显性负作用是RTH发病的关键机制。事实上，迄今为止已鉴定出60多种突变，但在编码与N-CoR相互作用的结构域的区域中没有报告突变。因此，我们研究了突变体TR中N-CoR结合位点的破坏是否会消除突变受体的显性负作用。结果表明，这种破坏消除了突变受体的显性负面作用。这表明突变体TR与N-CoR的结合是突变体受体显性负作用所必需的。3．视黄醇X受体(RXR)的细胞内降解目前公认TR通过与RXR形成异二聚体来发挥其作用。因此推测RXR的代谢可以改变TR的作用。我们证明RXR被组织蛋白酶-L型蛋白酶(一种溶菌体酶)快速降解。此外，研究还表明，抑制该酶会导致肝细胞对甲状腺激素的反应增强，说明RXR的代谢可以影响甲状腺激素的作用。 4．糖皮质激素对肝细胞中RXRa表达的调节肝脏中表达的主要RXR已被证明是RXRα。我们证明糖皮质激素可以增加RXRα的表达并增强甲状腺激素的作用，这表明糖皮质激素和甲状腺激素之间存在相互影响。5． TNFα对甲状腺激素作用的修饰已证明，TNFα激活的核因子κ-B(NF-κB)抑制肝脏中5'-脱碘酶基因的甲状腺激素依赖性激活。这项研究表明，TNFα 增加引起的甲状腺功能正常病态综合征的发生机制可能是肝脏中甲状腺激素作用的 NF-κB 依赖性抑制。较少的