Research mechanisms of Thyrotropin Receptor Expression

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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.