Physiology of the steroid-thyroid hormone nuclear receptor superfamily.

Glucocorticoids, other steroid hormones, thyroid hormones and vitamin-derived hormones (including retinoids) all exert their effects by the regulation of hormone-responsive target genes within the cell nucleus. These hormones bind to a series of specific nuclear receptor proteins that function as hormone-inducible transcription factors. The receptors are structurally homologous, are related to the avian erythroblastosis oncogene v-erbA, and exhibit remarkable evolutionary conservation. Together they form the steroid-thyroid hormone nuclear receptor superfamily. This chapter describes the structure and functions of the various family members and highlights the differences and similarities that occur between individual receptor proteins. Type I receptors, which include glucocorticoid receptor and other steroid receptor proteins, interact as homodimers with target sequences of DNA containing two receptor binding sites arranged as a palindrome. Type II receptors, which include receptors for retinoids, thyroid hormone and vitamin D3, bind as heterodimers (or homodimers) to DNA sequences in which two or more receptor-binding sites are arranged as a direct repeat or as other more complex configurations. The complexity of both receptor-DNA and receptor-receptor interactions predicts the potential for considerable cross-talk between various hormone-activated pathways. Thus, the specificity of hormone action and its regulation is discussed in relation to the structural and functional characteristics of the receptors and their molecular mechanisms of action. Finally, potential sites of regulation of hormone action, from circulating hormone levels in the periphery to their delivery to the cell and final site of action in the nucleus, are highlighted to provide a perspective for the following chapters in this volume and to indicate their clinical significance.