FUNCTION OF COFACTORS MODIFYING THYROID HORMONE RECEPTOR FUNCTION

1.人核辅阻遏子(HN-COR)HN-COR的染色体定位研究表明，HN-COR与去连接的甲状腺激素受体有关，并抑制甲状腺激素靶基因的转录。我们利用人和小鼠杂交细胞系进行荧光原位杂交和Southern印迹分析，将Hn-COR基因定位在染色体17q11.2上。这是关于Hn-CoR2基因定位的首次报道。N-COR在甲状腺激素抵抗(RTH)发病机制中作用的研究大多数情况下，RTH是以常染色体显性方式遗传的。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的显性负性作用是RTH发病的关键机制。迄今已发现60多个突变，在编码…结构域的区域没有发现突变。因此，我们研究了突变受体中N-COR结合位点的破坏是否取消了突变受体的显性负作用。结果表明，这种干扰消除了突变受体的显性负性作用。这表明突变受体的显性负性作用需要突变受体与N-COR结合。维甲酸X受体(RXR)的细胞内降解现在被认为是通过与RXR形成异二聚体来发挥作用的，因此推测RXR的代谢可以改变RXR的作用。我们证明RXR是通过一种组织蛋白酶-L类型的酶-溶菌体酶来快速降解的。此外，该酶的抑制导致肝细胞对甲状腺激素的反应增强，说明RXR的代谢可能影响甲状腺激素的作用。糖皮质激素对RXRA在肝细胞中表达的调节作用研究表明，在肝脏中表达的主要RXR为RXRα。我们发现糖皮质激素可增加RXRα的表达，增强甲状腺激素的作用，提示糖皮质激素与甲状腺激素之间存在相互作用。肿瘤坏死因子α对甲状腺激素作用的修饰核因子-κB可抑制5‘-脱碘酶基因在肝脏中的甲状腺激素依赖性激活。本研究提示，肿瘤坏死因子α升高引起的正常甲状腺病态综合征的发生机制可能与核因子-κB依赖抑制肝脏甲状腺激素的作用有关。较少

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