Thyroid hormone receptors (TRs) belong to a superfamily of nuclear hormone receptors including the steriod hormone, vitamin D, and retinoid receptors. They can bind as heterodimers with retinoid X receptors to hormone response elements (HREs) located in the promoter region of target genes. For positively-regulated genes, thyroid hormone (T3) binds to the receptor and increases transcription. Interestingly, in the absence of T3, TRs can still bind to HREs and repress transcription below basal level. There is emerging evidence on how the receptor mediates these effects. Recently, several groups have described co-activators and co-repressors that interact with the receptor in a ligand-dependent manner. Additionally, there are other proteins that interact with the liganded receptor/co-activator complex such as CBP and p/CAF which have intrinsic histone acetylase activity. Similarly, co-repressors have been shown to complex with histone deactylases. Far-western and co-transfection studies from our group have suggested there are multiple proteins that can interact with both the unliganded and liganded TR. The identity of most of these proteins which form the receptor complexes which mediate transcriptional activation and basal repression still are not known. Our goal is to use a number of techniques such as the yeast two-hybrid system, Far-Western analyses, and phage display to identify nuclear proteins that interact with thyroid hormone receptors and steroid hormone receptors. We also plan to study the protein-protein interactions of identified co-factors with receptors using in vitro, cell culture, and histological approaches. We also will examine the interaction of these and previously described co-factors with natural mutant TRs from patients with thyroid hormone resistance syndrome. Additionally, in related work, we will study the action of mutant receptors in specific tissues (particularly adipose tissue) of transgenic mice which we previously have created.
