Nuclear Receptors

Publisher Summary The first steroid hormone to be isolated, purified, and characterized was the estrous-inducing substance, estrin (C18H22O2) obtained in gram quantities from the urine of pregnant women. The steroid and thyroid hormones, and other lipophilic messengers are carried by specific binding proteins in the circulation. It has been thought that they penetrate cell membranes and enter cells passively, but this is not always the case. In the cytosol, most of them bind to intracellular receptor molecules that then migrate to the nucleus, attach to particular regulatory DNA sequences (response elements), and activate or inhibit transcription (transactivation or transrepression). The receptors for steroid hormones are members of a very much larger class of ligand-activated transcription factors. It includes the receptors for thyroid hormones, for retinoids (i.e., all-trans-retinoic acid or vitamin A, and its isomer 9–cis-retinoic acid) and for vitamin D (cholecalciferol). This family is called the nuclear receptor superfamily. Its members have a wide range of biological functions including the regulation of growth and embryonic development, the maintenance of phenotype, and the regulation of metabolic processes, such as cholesterol and bile acid metabolism. Disorders of these systems can lead to infertility, obesity, diabetes, and cancer. Over the years, the study and classification of nuclear receptors has suffered from the problem of multiple names for the same gene. A systematic nomenclature has therefore been established. The general structure of the nuclear receptors is highly conserved, consisting of a set of common functional domains. This chapter also discusses activation, interaction, and repression of transcription pathways by nuclear receptors and their other nontranscriptional actions.