Molecular Mechanisms of Nuclear Thyroid Hormone Action

Abstract

The role of thyroid hormone (L-triiodothyronine, T3; L-tetraiodothyronine, T4; TH) in the regulation of diverse cellular activities, including normal growth and development, and in general metabolism, is well established (1–4). TH exerts its major effects at the genomic level, although action at nongenomic sites such as the plasma membrane, cytoplasm, and mitochondrion is also evident (see Chap. 2). Much work in the field, especially over the past decade, has provided a better understanding of the molecular mechanisms involved in TH action and gene transcription (5,6). As illustrated in Fig. 1, circulating free TH enters the cell by either passive diffusion or other, yet poorly described mechanisms. In addition, the more biologically active T3 (triiodothyronine) may be generated from T4 (thyroxine) in some tissues by iodothyronine 5′-deiodinases, and both T3 and T4 may be subject to further intracellular inactivation. TH then enters the nucleus, where it binds to the nuclear thyroid-hormone receptor (TR) with high affinity and specificity with K d values in the nanomolar range). TR is a ligand-regulated transcription factor that is intimately associated with chromatin, and also associates with other nuclear proteins to form heterodimers. These in turn are bound to target DNAs known as TH-response elements (TREs). The formation of a liganded TR/DNA complex leads to activation of its associated gene, and to consequent changes in messenger RNA (mRNA) and protein. Thus, the central role of TR in the nuclear action of TH is evident.