glucocorticoid receptor gene
Interestingly, GR inhibits NF-κB-dependent transcriptional elongation, demonstrating that GR can act at steps after formation of the transcriptional initiation complex (Nissen and Yamamoto, 2000). (A) Genomic, complementary DNA, and protein structures of the human glucocorticoid receptor (hGR). The receptor then regulates gene transcription by binding directly to specific DNA sequences known as glucocorticoid response elements (GREs) and/or by binding other transcription factors and modulating their activity. They exist as homodimers coupled to Hsp90 or HMGB proteins, which are shed upon activation. These receptor isoforms possess unique expression, functional, and gene-regulatory profiles. Table 1. Glucocorticoids exert their effects by binding to a cytoplasmic GR that has several functional domains, including a ligand-binding domain, a DNA-binding domain, and two domains that are involved in transactivation of genes once binding to DNA has occurred via association with other proteins (activation function-1 and -2) (31). Like other members of the nuclear receptor superfamily, GR is a modular protein comprising an amino-terminal transactivation domain (NTD); a central, two-zinc-finger DNA-binding domain (DBD); and a carboxyl-terminal ligand-binding domain (LBD) (. UniProtKB. In vitro culture of mouse mammary epithelium also demonstrates the importance of glucocorticoids in acini formation (Murtagh et al., 2004). The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life. The A3669G-directed rise in GRβ may also compromise the immunosuppressive actions of GRα. The signal transducers and activators of transcription (STAT) family proteins function as DNA-binding transcription factors that are induced by growth factor signaling through transmembrane receptors and associated JAK kinases. Numbers shown denote the first and last residues for the human GR isoforms. P. Gass, in Encyclopedia of Stress (Second Edition), 2007. x; UniProtKB. These models can be used to study biological changes underlying the pathogenesis of depression. Upon binding glucocorticoids, GR undergoes a conformational change resulting in the dissociation of hsp90, exposure of the nuclear localization signals, and translocation of the receptor into the nucleus via the nuclear pore. The molecular weights of these receptor isoforms are 97 and 94 kDa, respectively. In contrast to AP-1 and NF-κB, the physical association of GR with the signal transducer and activator of transcription (STAT) family of proteins enhances their activity on target genes. Those readers interested in an in-depth review of all mutations in the GR gene are referred to the Glucocorticoid Receptor Resource (http://biochem1.basic-sci.georgetown.edu/grr/grr.html). Voss, in Hormones, Brain and Behavior (Second Edition), 2009. Steroids enter the target cell by passive diffusion, where they bind to the cognate receptor (MR). The traditional view that glucocorticoids exert these effects through one receptor isoform has changed dramatically in recent years with the discovery of a family of receptor isoforms arising from alternative processing of the single GR gene. In the formation of the GR–GR homodimer, the hinge region is sufficient to promote this dimerization in solution; peptides that mimic this region have been synthesized, and these peptides can associate with the GR to form a dimer. Buy Membership for Endocrinology, Diabetes and Metabolism Category to continue reading. Thus, two molecules of the GR would be associated in head-to-head fashion, allowing the DNA-binding domains of each to participate in binding the major groove in DNA. Gerald Litwack, in Encyclopedia of Hormones, 2003. In contradistinction to hGRα, hGRβ interacts poorly with hsps, resides primarily in the nucleus of cells independently of the presence of ligand, does not bind glucocorticoids or anti-glucocorticoids, does not activate glucocorticoid-responsive genes, and is transcriptionally inactive. A blunted immune response leaves the door open for potentially fatal infections, whereas an overstimulated immune response can result in autoimmune activity that damages organs. Click to share on Twitter (Opens in new window), Click to share on Facebook (Opens in new window), Click to share on Google+ (Opens in new window), Presurgical Functional MappingAndrew C. Papanicolaou, Roozbeh Rezaie, Shalini Narayana, Marina Kilintari, Asim F. Choudhri, Frederick A. Boop, and James W. Wheless, the Child With SeizureDon K. Mathew and Lawrence D. Morton, and Pharmacologic Consequences of SeizuresShilpa D. Kadam and Michael V. Johnston, Self-Limited EpilepsiesDouglas R. Nordli, Jr., Colin D. Ferrie, and Chrysostomos P. Panayiotopoulos, in Epilepsy: A Network and Neurodevelopmental PerspectiveRaman Sankar and Edward C. Cooper, Hematology, Oncology and Palliative Medicine. These include the development of glucocorticoid resistance in diseased tissues, osteoporosis, growth retardation in children, muscle atrophy, and signs of the metabolic syndrome.1,4,5 The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of proteins that regulate gene transcription in a ligand-dependent manner.6 In this section, we review the basic mechanisms of glucocorticoid action with an emphasis on how these mechanisms contribute to the antiinflammatory and immunomodulatory effects of glucocorticoids.