Regulation of gene expression by thyroid hormone.

The thyroid hormones (3,5,3',5'-tetraiodo-L-thyronine [L-T4]' and 3,5,3'triiodo-L-thyronine [L-T3]) have marked effects on the growth, development, and metabolic function of virtually all organ systems and tissues ofhuman beings and other higher organisms (1-3). L-T4 was one of the first hormones to be isolated and its structure determined (4-6). Several decades later L-T3 was identified in the circulation (7-9). Although L-T3 is secreted by the thyroid gland, a significant amount is derived from peripheral conversion of L-T4 to L-T3 by 5'deiodinases in various tissues (10). L-T3 is about 10-fold more active than L-T4 on a molar basis (3). Because of its higher intrinsic biologic activity, its conversion from L-T4 in various tissues, and its lower affinity for serum binding proteins, L-T3 plays a more dominant role than L-T4 in maintaining the normal euthyroid state (2). Because of the marked alterations in the rate of oxygen consumption identified in hypothyroidism and hyperthyroidism, initial studies on the mechanism of action ofthe thyroid hormones were focused on mitochondrial function. In vitro studies indicated that iodothyronines could alter the function of isolated mitochondria (1, 1 1). However, this occurred only at iodothyronine concentrations 100,000fold higher than those found in the euthyroid state, and L-T3 was less active than L-T4 (1 1). In the 1960s Tata and co-workers showed that thyroid hormone administration increased the rate of RNA synthesis in rat liver suggesting that L-T3 and L-T4 might act by controlling gene expression (12, 13). Research over the past decade using intact animals and cultured cells has provided compelling evidence that the thyroid hormones exert their effects in various cells and tissues by stimulating the accumulation of mRNAs which code for specific proteins. The following thyroid hormone-dependent effects have been studied in detail: stimulation of growth hormone synthesis in the rat anterior pituitary in vivo (14); regulation of growth hormone gene expression in cultured rat pituitary cell lines (15-24); stimulation