Biological activities of thyroid hormone receptors.

In recent years a large amount of data has been gathered on the biology of thyroid hormone receptors. The receptor proteins have been analyzed from the physiological and structural points of view. Most of the information has been summarized in several recent excellent reviews (1–6). The thyroid hormone receptors (TR) are ligand-modulated transcription factors which are members of a large superfamily that includes nuclear receptors for other small, hydrophobic molecules such as steroids, vitamin D3, retinoic acid, prostaglandins, terpenoids, farnesoids and fatty acids, and also the so-called orphan receptors with no recognizable ligand. They bind triiodothyronine (T3) with an affinity about 10 times higher than thyroxine (T4) and activate or repress gene expression upon ligand binding. In addition, an important property of the thyroid hormone receptors is their ability to influence gene expression in the absence of the hormone. In most cases this is reflected in a repression of the target genes which is relieved upon ligand binding, although there are also examples of ligand-independent stimulation of transcription. Little is known of the biological consequences of this intrinsic receptor property. The repressor activity of mutated T3 receptors that have lost the ability to bind hormone is considered to play a role in the pathogenesis of the thyroid hormone resistance syndromes. Receptor expression during development precedes the onset of fetal thyroid function and, with the reservations imposed by placental transfer of maternal thyroid hormone, the unliganded receptor might influence fetal development through mechanisms that are at present unknown. To shed light on this problem, we and others have analyzed the influence of exogenous T3 receptor expression on the phenotype of cultured cells which express no or little T3 receptors unless engineered to do so. The purpose of this review is to summarize the available data in this direction and to try to formulate an hypothesis concerning receptor function.