Gene regulation by thyroid hormone receptors

During the first decade since the thyroid hormone receptors were cloned as homologues of v-erbA, many promoters regulated by these receptors were identified, and the importance of ligand-dependent and ligand-independent differential control of gene expression was established. In this review, we discuss some reports that mark the inception of the second decade of thyroid hormone receptor research as one in which a clear understanding of the molecular mechanisms of receptor action is likely to be achieved. Solving the crystal structure of the liganded thyroid hormone receptor has provided a conceptual basis for understanding the protein interactions that modulate the gene activation program of nuclear receptors. Many potential cofactors of the thyroid hormone receptor have now been characterized and cloned, providing the next level of definition of the complex regulation of positive and negative control of gene expression. Furthermore, evidence has been obtained for direct interactions between the proteins of the basic poly-merase II transcription machinery with the thyroid hormone receptor that could be responsible for the ligand-independent repression in in vitro systems.