The coregulator exchange in transcriptional functions of nuclear receptors

  1. Christopher K. Glass1 and
  2. Michael G. Rosenfeld2,3
  1. 1Department of Cellular and Molecular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0651 USA; 2Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California 92095-0648 USA

This extract was created in the absence of an abstract.

Nuclear receptors (NR) comprise a family of transcription factors that regulate gene expression in a ligand-dependent manner. Members of the NR superfamily include receptors for steroid hormones, such as estrogens (ER) and glucocorticoids (GR), receptors for nonsteroidal ligands, such as thyroid hormones (TR) and retinoic acid (RAR), as well as receptors that bind diverse products of lipid metabolism, such as fatty acids and prostaglandins (for review, see Beato et al. 1995; Chambon 1995;Mangelsdorf and Evans 1995). The NR superfamily also includes a large number of so-called orphan receptors for which regulatory ligands have not been identified (Mangelsdorf and Evans 1995). Although many orphan receptors are likely to be regulated by small-molecular-weight ligands, other mechanisms of regulation, such as phosphorylation (Hammer et al. 1999; Tremblay et al. 1999) have also proven to be of importance. Remarkably, the sequence of the Caenorhabditis elegans genome has revealed the presence of >200 members of the NR family, suggesting a critical role of these proteins in environmental adaptation (Sluder et al. 1999). Although mammalian genomes are unlikely to contain such a large complement of these factors, >24 distinct classes of NR have been identified in humans, and these factors exert diverse roles in the regulation of growth, development, and homeostasis. Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level.

Members of the NR family regulate transcription by several mechanisms (Fig. 1). Nuclear receptors can activate or repress target genes by binding directly to DNA response elements as homo- or heterodimers or by binding to other classes of DNA-bound transcription factors. A subset of NRs, including TR and RAR, can actively repress target genes in the …

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