The mechanism of action of thyroid hormones

(T)hyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid horm one receptors belong to a nuclear receptor superfamily that also includes r eceptors for other small lipophilic hormones. Thyroid hormone receptors fun ction by binding to specific thyroid hormone-responsive sequences in promot ers of target genes and by regulating transcription. Thyroid hormone recept ors often form heterodimers with retinoid X receptors. Heterodimerization i s regulated through distinct mechanisms that together determine the specifi city and flexibility of the sequence recognition. Amino-terminal regions ap pear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histon e deacetylase. Ligand binding alters the conformation of the thyroid hormon e receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, in cluding a steroid receptor family coactivator, p300/CREB-binding protein-as sociated factor (PCAF), and CREB binding protein (CBP). The existence of hi stone-modifying activities in the transcriptional regulatory complexes indi cates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to b e understood, as are aspects of the tissue specificity of hormone action. M oreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understand ing of the structure and function of thyroid hormone receptors and their in teracting proteins has markedly clarified the molecular mechanisms of thyro id hormone action.