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Research mechanisms of Thyrotropin Receptor Expression

促甲状腺素受体表达的研究机制

基本信息

批准号：
08671169
负责人：
IKUYAMA Shoichiro
金额：
$ 1.28万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

In a previous project, we have characterized structure and function of the promoter region of the rat thyrotropin (TSH) receptor gene, and identified several cis-acting elements and trans-acting factors which regulate the expression of the gene in thyroid. One of notable findings is that a transcription factor TSEP-1/YB-1, which acts on major histocompatibility complex class II gene as a repressor, also functions as a repressor on the TSH receptor promoter. Based on these studies, we further analyzed the promoter region and factors interacting with it in the present project.We further cloned and characterized -4.2 kb region of the rat TSH receptor promoter. The -4.2 kb region exhibited less promoter activity than that of the minimal promoter region which we already analyzed, supporting the importance of the minimal promoter region on the activity. There are many putative TSEP-1/YB-1 binding sites, which function as a repressor, in the upstream region. These elements may suppress the promoter activity constitutively.Aberrant expression of MHC class II antigen on thyroid cells is important for induction and perpetuation of autoimmune reaction in autoimmune thyroid diseases (AITD). TSH receptor itself is also important as an autoantigen. To control the expression of TSH receptor and MHC class II on thyroid cells, we focused on the action of TSEP-1/YB-1 on both genes. We showed that nicotinamide potentiated promoter activity of both genes, and this was attributed a dose-dependent reduction of TSEP-1/YB-1 expression induced by nicotinamide. This result does not directly implicate a therapeutic value of nicotinamide, but suggests the presence of agents which may regulate the expression of both genes simultaneously. If there were such agent which could repress the expression of TSH receptor and MHC class II on thyroid cells, it could be beneficial for treatment of AITD such aS Graves' disease. We are pursuing this possibility in the future project.

在以前的一个项目中，我们的特点是结构和功能的大鼠促甲状腺激素（TSH）受体基因的启动子区，并确定了几个顺式作用元件和反式作用因子，调节基因在甲状腺中的表达。一个值得注意的发现是，作为阻遏物作用于主要组织相容性复合体II类基因的转录因子TSEP-1/YB-1也作为阻遏物作用于TSH受体启动子。在此基础上，本课题进一步分析了促甲状腺激素受体启动子区及其相互作用因子，并进一步克隆了大鼠促甲状腺激素受体启动子区-4.2kb的片段。与我们已经分析的最小启动子区域相比，~ 4.2kb区域表现出较低的启动子活性，这支持了最小启动子区域对活性的重要性。在上游区域存在许多推测的TSEP-1/YB-1结合位点，其作为阻遏物起作用。MHC Ⅱ类抗原在甲状腺细胞上的异常表达对自身免疫性甲状腺疾病（AITD）自身免疫反应的诱导和持续具有重要意义。TSH受体本身作为自身抗原也很重要。为了控制甲状腺细胞上TSH受体和MHC II类的表达，我们集中研究了TSEP-1/YB-1对这两个基因的作用。我们发现烟酰胺增强了两个基因的启动子活性，这归因于烟酰胺诱导的TSEP-1/YB-1表达的剂量依赖性降低。该结果并不直接暗示烟酰胺的治疗价值，但表明存在可同时调节两种基因表达的试剂。如能抑制甲状腺细胞上TSH受体和MHC Ⅱ类分子的表达，将有助于Graves病等AITD的治疗。我们在未来的项目中正在探索这种可能性。