Thyroid hormone (T3) is crucial for normal growth, development, and adult function. Nuclear T3 receptor (TRs) regulated transcription of specific genes in a T3-dependent manner. There are three distinct TRs which bind to T3-response elements (TREs) in target genes as monomers, homodimers, and heterodimers with retinoid X receptors (RXRs) and other proteins. There are also C-terminal TR variants which do not bind T3 but are inhibitors of T3 action. It is presumed that the multiple TR isoforms and heterodimer partners are responsible for the tissue-specific and diverse effects of T3. The goal of this research is to specifically relate TR expression and biochemistry to the cellular and molecular physiological effects of T3. The first specific aim of this project is to study the hormonal regulation of TRbeta2 mRNA and protein expression in pituitary and neural cell lines. Of particular importance is the ability of RA to antagonize the down-regulation of TRbeta2 by T3. RXR- specific ligands will be used to discover the mechanism underlying this hormonal cross-talk. The second specific aim is to address the molecular physiology to T3 actio using the technique of differential display. Novel T3-responsive target genes will be identified and characterized according to how they are regulated positively or negatively; by both T3 and RA or by T3 alone; and universally or i a cell-specific manner. In this way, the rules governing positive vs. negative regulation, hormonal specificity vs. promiscuity, and cell-specificity of T3 action will be clarified. The third specific aim is to compare and contrast the TRE- binding properties of TR monomers, homodimers, and heterodimers. These TR, and correlate these biochemical properties with transcriptional function. The fourth specific aim is to understand the function and significance of C-terminal TR variants, alpha2 alpha3. The DNA-binding and transcriptional regulatory properties of these proteins will be determined and contrasted. The ability of phosphorylation to regulate the functions of TRalpha2 and alpha3 will be investigated, to address the paradox that TRalpha2 is highly expressed (especially in brain) yet binds DNA poorly in vitro and is a weak inhibitor of T3 action. Together, these studies will link the molecular biology and biochemistry of the TRs to the cellular and physiological responses to T3. This knowledge will provide insight into hormone action in general, and enhance understanding of many pathophysiological states including thyroid hormone deficiency and excess, genetic resistance to thyroid hormone, and hormone-responsive malignancies, such as breast cancer, prostate cancer, and promyelocytic leukemia.
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