Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Pharmacological Reviews
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Pharmacological Reviews

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit Pharm Rev on Facebook
  • Follow Pharm Rev on Twitter
  • Follow ASPET on LinkedIn
Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Nick Z. Lu, Suzanne E. Wardell, Kerry L. Burnstein, Donald Defranco, Peter J. Fuller, Vincent Giguere, Richard B. Hochberg, Lorraine McKay, Jack-Michel Renoir, Nancy L. Weigel, Elizabeth M. Wilson, Donald P. McDonnell and John A. Cidlowski
Pharmacological Reviews December 2006, 58 (4) 782-797; DOI: https://doi.org/10.1124/pr.58.4.9
Nick Z. Lu
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suzanne E. Wardell
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kerry L. Burnstein
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald Defranco
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter J. Fuller
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vincent Giguere
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard B. Hochberg
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lorraine McKay
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jack-Michel Renoir
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nancy L. Weigel
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth M. Wilson
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald P. McDonnell
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John A. Cidlowski
Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina (N.Z.L., J.A.C.); Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (S.E.W., D.P.M.); Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.L.B.); University of Pittsburgh School of Medicine, Department of Pharmacology, Pittsburgh, Pennsylvania (D.D.); Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia (P.J.F.); Royal Victoria Hospital, Molecular Oncology Group, Montreal, Quebec, Canada (V.G.); Yale University School of Medicine, New Haven, Connecticut (R.B.H.); Bristol-Myers Squibb, Immune Cell Function Group, Princeton, New Jersey (L.M.); Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, Chatenay-Malabry, France (J.-M.R.); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (N.L.W.); and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.M.W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Introduction

The glucocorticoid receptor (GR1), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR) are classic members of the nuclear receptor superfamily, composing subfamily 3C. Members of this subfamily are among those receptors that were cloned the earliest, with the GR being cloned in 1985 and the MR, PR, and AR shortly thereafter (Hollenberg et al., 1985; Arriza et al., 1987; Misrahi et al., 1987; Chang et al., 1988; Lubahn et al., 1988). Individually and in combination, these four receptors play pivotal roles in some of the most fundamental aspects of physiology such as the stress response, metabolism, immune function, electrolyte homeostasis, growth, development, and reproduction.

Multiple signaling pathways have been established for all four receptors, and several common mechanisms have been revealed (Mangelsdorf et al., 1995). One main signaling pathway is via direct DNA binding and transcriptional regulation of responsive genes. Another is via protein-protein interactions, mainly with other transcription factors such as nuclear factor-κB, activator protein-1, or signal transducer and activator of transcriptions, to regulate gene expression patterns. Both pathways can up-regulate or down-regulate gene expression. Both pathways require ligand activation of the receptor and interplay with multiple protein factors such as chaperone proteins and coregulator proteins (Lonard and O'Malley, 2005).

These four steroid hormone receptors also exemplify the tremendous capacity and precision of endocrine modulatory mechanisms. Patients carrying mutated receptors frequently experience severe complications, and transgenic animals lacking individual receptors frequently cannot reproduce and/or survive (Cole et al., 1995, 2001; Lydon et al., 1995; Quigley et al., 1995; Berger et al., 1998; Tajima et al., 2000; Bray and Cotton, 2003; Sato et al., 2003; Sartorato et al., 2004; Lin et al., 2005; Matsumoto et al., 2005). Temporally controlled tissue distribution patterns during developmental stages, reproductive phases, and disease states contribute to the diverse activities of these receptors. Recently, exciting new information has emerged regarding these receptors, such as their structures, domain interactions, coregulatory partners, multiple isoforms, post-translational modifications, and synthetic selective modulator ligands, which show promise for new effective therapeutic approach.

Structure

The GR, MR, PR, and AR share structural similarities, with all containing three functional domains, i.e., the N-terminal transactivation domain followed by the DNA-binding domain (DBD) and the C-terminal ligand-binding domain (LBD) (Mangelsdorf et al., 1995). A hinge region links the DBD and the LBD. Compared with the GR, the sequence identities of the N-terminal domains of the MR, PR, and AR are 38, 24, and 16%, of the DBDs are 94, 91, and 79%, and of the LBDs are 57, 54, and 51%, respectively (Hollenberg et al., 1985; Arriza et al., 1987; Misrahi et al., 1987; Chang et al., 1988). Overall sequence identities for each receptor among different species (human, rat, and mouse) are between 81 and 97%.

The crystal structure of the DBD was solved for the GR (Luisi et al., 1991). The structures of the DBDs for other receptors can be inferred on the basis of the high degree of similarity of this domain among this group of receptors. Several unique features contribute to the ability of the GR DBD to bind specifically to its target DNA recognition sequences, termed glucocorticoid-response elements (GREs). The GR DBD has a single globular domain containing two perpendicular α helices, one of which is responsible for specific DNA recognition and together with the other α helix forms the cross-shaped hydrophobic core of the DBD. At the N terminus of each helix, a zinc ion coordinated by four cysteine residues in a tetrahedral geometry holds the peptide loops. The DBD, which is monomeric and unstructured in solution, dimerizes in a head-to-head orientation when it binds to DNA with the recognition helices of each DBD in adjacent major grooves of the DNA. This accounts for the cooperative binding of two DBD domains to the GRE. The precise chemistry of the protein-protein and the protein-DNA interfaces has also been elucidated (Luisi et al., 1991). The protein is anchored to the phosphate backbone with seven contacts on either side of the major groove. The DNA-recognition helix makes three van der Waals contacts between a valine and the methyl group of a thymine. Classic GREs consist of two hexameric inverted repeat half-sites separated by a 3-base pair spacer. The sequence of the half-sites determines which receptor can be recognized specifically. In nonspecific binding, the contacts made between the receptor and DNA are rearranged and fewer in number. In addition, gene-specific GR-GRE interactions have been reported. For example, it has been reported that a GR trimer binds to the pro-opiomelanocortin promoter and exerts transcription repression (Drouin et al., 1993); composite GREs recruit additional transcription factors that determine the direction of GR-mediated transcription of the proliferin gene (Diamond et al., 1990); GR forms a heterodimer with other steroid hormone receptors such as MR (Calle et al., 2003; Funder, 1993; Trapp and Holsboer, 1996) and AR (Chen et al., 1997) on some other GREs.

The crystal structures for the LBD of the GR, MR, PR, and AR have been made available through work from several groups (Williams and Sigler, 1998; Matias et al., 2000; Bledsoe et al., 2002, 2005; Kauppi et al., 2003; Fagart et al., 2005; Li et al., 2005). Remarkable similarities as well as some unique features have been identified, providing strong evidence for several important aspects of receptor function including ligand selectivity, receptor dimerization, and coactivator recruitment. One of the common features of the LBDs of the GR, MR, PR, and AR is the structural composition and organization. Each LBD contains 11 α helices (designated helix 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) and four small β strands that fold into a three-layer helical sandwich. The region between helices 1 and 3 is unstructured in the steroid receptors, in contrast to the other nuclear receptors from which the nomenclature derives. Helices 1 and 3 form one side of the sandwich, and helices 7 and 10 form the other side. The middle layer (helices 4, 5, 8, and 9) is arranged at the upper half of the LBD, delimiting a hydrophobic cavity underneath where the steroid molecule is bound. Toward the C terminus, the activation function (AF)-2 helix, helix 12 packs against helices 3, 4, and 10 as an integrated part of the domain structure. Following helix 12 is an extended β strand that forms a β sheet together with a β strand between helices 8 and 9. Thus, the ligand-binding pocket has a scaffold framed by multiple helices and the first two β strands. The cognate steroid ligand for each receptor is completely buried within the ligand-binding pocket. Three structural features ensure ligand selectivity. First, the unique hydrogen bond network between the receptor and the bound ligand establishes specific recognition between the cognate ligand and receptor. For example, the MR ligand-binding pocket contains a unique polar surface absent in the other receptors, which is critical for specific binding of aldosterone. Second, the shape of the steroid and the topology inside the binding pocket enhance selectivity. The GR ligand-binding pocket contains a branched side pocket due to a proline residue in the linker between helices 6 and 7, which is critical for high-affinity binding of glucocorticoids to the GR. Third, the relative position of the binding pocket within the receptor LBD plays a role in ligand selectivity. Compared with the other receptors, the AR ligand-binding pocket seems to be shifted up toward helices 1 and 3, which contributes to selectivity of the AR for androgens. The relative position of the ligand-binding pocket provides a structural basis for the importance of residues outside of the pocket, which are critical for the integrity of the LBD (Rogerson et al., 1999).

Another common feature of the LBD among steroid receptors is the presence of the coactivator-binding cleft on the surface of the LBD above the ligand-binding pocket (Williams and Sigler, 1998; Matias et al., 2000; Bledsoe et al., 2002; Li et al., 2005). This AF-2 binding site is essential for the ligand-dependent recruitment of a wide variety of coactivators that determine transcriptional activity of the receptor. Specific charged residues termed charge clamps and intermolecular interactions facilitate relative cofactor selectivity by each receptor. A common motif among the coactivators that interacts with these charge clamp residues is the leucine-rich LxxLL motif (Lonard and O'Malley, 2005). The AR, however, prefers FxxLF motifs and interacts with lower binding affinity with the LxxLL-containing cofactors such as steroid receptor coactivator 1 (SRC-1) (He et al., 2002, 2004).

Structures of the N-terminal variable regions are not available to date for any of the receptors in this subfamily. Recent work from several laboratories suggests that this domain possibly folds into an organized structure and interacts with the C terminus of the receptor through specific intra- and intermolecular interactions (Langley et al., 1998; He et al., 1999; Tetel et al., 1999; Rogerson and Fuller, 2003). A glutamine-rich region in the AR N terminus is necessary and sufficient for recruiting coactivators such as SRC-1 (Bevan et al., 1999). Polymorphisms such as glutamine-rich tracts of abnormal length in the AR result in molecular changes and neurological disease (Poletti, 2004). Further work is needed to shed light on the molecular organization of this important domain that contributes to the transcriptional activity of the receptor.

Endogenous Ligands and Their Functions

The major glucocorticoid in the human is cortisol, also called hydrocortisone, whereas in rodents the major glucocorticoid is corticosterone. The synthesis and secretion of glucocorticoids by the adrenal cortex are tightly regulated by the hypothalamo-pituitary-adrenal axis, which is sensitive to negative feedback by circulating hormones and exogenous glucocorticoids. Healthy individuals secrete 10 to 20 mg of cortisol daily (Katzung, 2004; Goodman et al., 2006). The rate of secretion follows a circadian rhythm governed by pulses of pituitary hormone corticotropin (ACTH). In plasma, cortisol is bound to circulating proteins, such as corticosteroid-binding globulin (CBG) that binds 90% of the circulating hormone under normal circumstances. The remaining cortisol is free or loosely bound to albumin and is available to exert its effects on target cells. CBG is increased in pregnancy, by estrogen administration, and in hyperthyroidism. Synthetic glucocorticoids such as dexamethasone are largely bound to albumin rather than CBG.

GR is expressed in almost all tissues although tissue- and cell cycle-specific regulation of GR levels have been reported (Cidlowski et al., 1990; Oakley et al., 1996; Lu and Cidlowski, 2005). Glucocorticoids exert a vast array of physiological functions via the GR. Glucocorticoids are important regulators of carbohydrate, protein, and fat metabolism (Katzung, 2004; Goodman et al., 2006). In the fasting state, glucocorticoids stimulate gluconeogenesis and glycogen synthesis via a variety of mechanisms including increasing the production of enzymes critical in gluconeogenesis, stimulating the release of amino acids from muscles, promoting insulin resistance in the peripheral tissues, and inhibiting adipokines such as adiponectin. These processes protect glucose-dependent tissues such as the brain and heart during starvation. Glucocorticoids also profoundly modulate immune responses by regulating the activity of peripheral leukocytes, by suppressing the production of cytokines and chemokines, and by changing the life span of immune cells. In addition, glucocorticoids are critical for the functions of the central nervous system (CNS), digestive, hematopoietic, renal, and reproductive systems. The development of fetal lung is dependent on glucocorticoids.

The most physiologically important mineralocorticoid is aldosterone. Aldosterone is synthesized in the adrenal cortex primarily under the regulation of the renin-angiotensin system, potassium status, and ACTH. Aldosterone is secreted at the rate of 100 to 200 μg/day in normal individuals with a moderate dietary salt intake and does not seem to be tightly bound to serum proteins (Katzung, 2004; Goodman et al., 2006). MR is expressed in epithelial tissues, such as the distal nephron or colon (Krozowski and Funder, 1983). Vectorial sodium reabsorption is driven by a mechanism coupling the apical epithelial sodium channel to sodium-potassium ATPase, the basolateral sodium pump. Both the epithelial sodium channel and Na+,K+-ATPase subunit genes are differentially regulated by aldosterone (Verrey et al., 1987; Kolla et al., 1999; Amasheh et al., 2000; Epple et al., 2000; Kolla and Litwack, 2000). Consequently, aldosterone promotes the reabsorption of sodium from the distal convoluted and cortical collecting renal tubules. Sodium reabsorption in the sweat glands, salivary glands, and gastrointestinal mucosa can also be increased by aldosterone. Thus, aldosterone is a critical regulator of serum sodium and other electrolytes and of cardiovascular tone. Interestingly, MR expression and function extend to nonepithelial cells such as hippocampal and hypothalamic neurons, cardiomyocytes, the vasculature, and adipocytes, with studies reporting both physiological and pathophysiological roles of MRs at these additional sites emerging (de Kloet et al., 2000; Funder, 2004). The MR is unique in that it is the receptor for two physiological ligands, aldosterone and cortisol (or corticosterone in rodents). Both have a similar affinity for MRs and, therefore, given the much higher circulating concentration, cortisol might be expected to exclusively occupy MRs. In epithelial and vascular tissues this occupation is prevented by the presence of the enzyme 11β-hydroxysteroid dehydrogenase 2, which converts cortisol to the inactive metabolite, cortisone. Inhibition of this enzyme by mutation or ingestion of inhibitors such as licorice or carbenoxolone results in inappropriate MR activation and hypertension. In other tissues such as the heart and selected areas in the CNS, the MR may act as a receptor for cortisol.

Progesterone is the most important progestin in humans. It is synthesized in the ovary, testis, and adrenal gland from circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy. In the ovary, progesterone is produced primarily by the corpus luteum. In addition to having important hormonal effects, progesterone serves as a precursor in the synthesis of estrogens, androgens, and adrenocortical steroids. Normal males seem to secrete 1 to 5 mg of progesterone daily (Katzung, 2004; Goodman et al., 2006). The progesterone level is only slightly higher in the female during the follicular phase of the menstrual cycle. During the luteal phase of the cycle and in the third trimester of pregnancy, the rate of progesterone secretion increases to 10 to 20 mg/day and to several hundred milligrams during the latter part of pregnancy. In plasma, 90% or more of total progesterone is bound by albumin and CBG. PR is expressed in the female reproductive tract, mammary gland, brain, and pituitary gland (Mangal et al., 1997; Soyal et al., 2005). In many cells, estrogens induce expression of PR, and its presence is a common marker for estrogen action in both research and clinical settings. In many biological systems, progestins enhance differentiation and oppose the cell proliferation action of estrogens. The unequivocal roles of progesterone in a variety of events such as ovulation, implantation, mammary gland development, maintenance of pregnancy, and behavior are well established. Progesterone also increases the ventilatory response of the respiratory centers to carbon dioxide and decreases arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy. Progesterone has depressant and hypnotic actions in the CNS, which may be mediated via inhibitory neurotransmitter receptors. Accumulating data indicate a role for progesterone in male reproductive events (Gadkar-Sable et al., 2005).

In humans, the predominant androgen secreted by the testis is testosterone. In men, ∼8 mg of testosterone is produced daily (Katzung, 2004; Goodman et al., 2006). In women, 0.25 mg of testosterone is synthesized by the ovary and by peripheral conversion of androstenedione produced by the adrenal gland. Alterations in plasma concentrations of testosterone and androstenedione occur during the menstrual cycle. In some ovarian disorders, androgens secreted by the ovary can be elevated, resulting in partial virilization. The concentration of testosterone in the plasma of males is relatively high during three periods of life: during embryonic development, during the neonatal period, and from puberty throughout adult life. The androgen concentration starts to rise in male embryos in approximately the 8th week of development and declines before birth. Androgen rises again during the neonatal period and then falls to typical prepubertal values within the first year of life. Plasma testosterone increases again at the time of male puberty and is maintained at the adult level until it declines gradually in senescence. Approximately 40 to 65% of circulating testosterone is bound to sex hormone-binding globulin (SHBG). SHBG is increased in plasma in response to estrogen and thyroid hormone and in patients with cirrhosis of the liver. SHBG levels are decreased by androgen and growth hormone and are lower in obese individuals. Most of the remaining testosterone is bound to albumin. Approximately 2% remains free and available to enter cells and bind to intracellular AR. In AR-target tissues such as prostate and skin, testosterone is reduced at the 5α position to 5-dihydrotestosterone, which serves as the active hormone (Auchus, 2004). Unlike other steroid receptors, AR is stabilized by high-affinity binding of testosterone or 5-dihydrotestosterone that induces the N-terminal FxxLF motif binding to the AF-2 in the LBD (Langley et al., 1998; He et al., 1999). 5-Dihydrotestosterone dissociates more slowly than testosterone from AR and thereby more effectively stabilizes the AR complex.

Androgens serve critical functions at different stages of life in the male (Katzung, 2004; Goodman et al., 2006). During embryonic life, androgens virilize the urogenital tract of the male embryo, and their action is thus essential for the development of the male phenotype. Lack of a fully functioning AR due to naturally occurring mutations in the male fetus results in incomplete male genital development or a female external phenotype (Quigley et al., 1995). The role of the neonatal surge of androgen secretion is not well defined, but it may contribute to developmental functions within the CNS. At puberty, androgens stimulate the development of secondary sexual characteristics. The growth-promoting properties of androgen increase height and the development of the skeletal musculature. In addition to stimulating and maintaining sexual function in men, androgens may also be responsible in part for aggressive behaviors. Androgens have critical physiological roles in women as well. Testosterone and androstenedione are precursors for estrogen biosynthesis; testosterone and 5-dihydrotesterone also produce androgenic effects via the AR.

Therapeutic Uses and Limitations

For several years, compounds targeting GR functions have been among the most frequently prescribed drugs. This is mainly due to immunomodulatory actions of glucocorticoids and their use in infections, allergies, eye diseases, hematological disorders, pulmonary diseases, skin diseases, inflammatory conditions of bones and joints, and acute respiratory distress syndrome (Katzung, 2004; Goodman et al., 2006). In addition, glucocorticoids are a key to treating certain leukemias and are frequently included in chemotherapy regimens for their antiemetic, antiedema, and palliative properties. GR agonists are also the mainstay in the management of congenital adrenal hyperplasia and Addison's disease (adrenal insufficiency), in diagnostic tests for Cushing's syndrome (adrenal hyperfunction), and in certain psychiatric conditions. Furthermore, glucocorticoids are the treatment of choice for impending premature parturition to accelerate neonatal lung maturation. RU-486, a potent GR antagonist, causes generalized glucocorticoid resistance. In Cushing's syndrome caused by ectopic ACTH production or adrenal carcinoma, RU-486 can reverse the symptoms, ameliorate glucose intolerance, and normalize blood pressure. Multiple mechanisms contribute to the antagonistic actions of RU-486 with the GR (Rhen and Cidlowski, 2005). Binding of RU-486 with GR stabilizes the heat shock protein (HSP)-GR complex and alters the interaction of GR with coregulators, which together result in the formation of transcriptionally inactive GR molecules.

Prolonged glucocorticoid therapy causes serious side effects (Rhen and Cidlowski, 2005). Osteoporosis, metabolic syndrome, impaired development, and blunted growth all limit chronic use of glucocorticoids. Patients receiving long-term glucocorticoid treatment experience redistribution of body fat from the extremities to the trunk and face. Neural and psychological disturbances, such as psychosis, depression, and euphoria, can occur. To reduce these untoward actions of glucocorticoids, the lowest dosage with therapeutic efficacy, intermittent administration, and localized routes of administration have been implemented with some success (Buttgereit et al., 2005).

Dysregulation of the MR-aldosterone system reveals its importance in various human pathological conditions such as mineralocorticoid resistance, disorders of the CNS, hypertension, and cardiac failure (Katzung, 2004; Goodman et al., 2006). MR agonists such as fludrocortisone are used in the treatment of adrenal insufficiency. MR antagonists such as spironolactone and eplerenone are used for the treatment of hypertension, excess urine protein excretion, and heart failure. The potassium-sparing properties of spironolactone and eplerenone can be life-threatening if hyperkalemia develops (Sica, 2005).

The two most frequent uses of progestins are for contraception, either alone or with an estrogen in oral contraceptives, and for hormone replacement therapy when combined with estrogen in postmenopausal women (Katzung, 2004; Goodman et al., 2006). Progestins are also used in several settings for ovarian suppression, e.g., dysmenorrhea, endometriosis, hirsutism, and uterine bleeding. In addition, progesterone can be used diagnostically to test for estrogen secretion and for responsiveness of the endometrium. Progestins have been used as a palliative measure for metastatic endometrial carcinoma and in the treatment of renal and breast carcinoma. The presence of the PR is considered a useful prognostic marker in breast cancer irrespective of the patient's progestational status. Contraception with progestins is useful in patients with hepatic disease, hypertension, psychosis, or mental retardation. The side effects include headache, dizziness, weight gain, and glucose intolerance. Recent studies suggest that certain progestin plus estrogen replacement regimens in post-menopausal women may increase the incidence of breast cancer, a finding that may promote the development of improved hormone replacement therapy (Rossouw et al., 2002).

The GR antagonist RU-486 is also a potent PR antagonist. RU-486 binds to PR with high affinity and can terminate pregnancy (Schreiber and Creinin, 2005). RU-486 has effects on ovulation as well. If given acutely in the mid to late follicular phase of the menstrual cycle, RU-486 delays follicle maturation and the luteinizing hormone surge, and ovulation occurs later than normal. If the drug is given intermittently or continuously, ovulation is prevented in most but not all cases. These effects are largely due to actions on the hypothalamus and pituitary rather than the ovary. RU-486 may produce effects on the cervix, myometrium, ectopic endometrial tissue (i.e., endometriosis), certain types of breast cancer, and meningiomas via its antiprogestin activity. RU-486 has been used as a postcoital contraceptive, and it may be slightly more effective than high-dose estrogen-progestin combinations. The mechanism of action in this case is thought to be prevention of implantation. Other investigational or potential uses for RU-486 include the induction of labor after fetal death or at the end of the third trimester and treatment of endometriosis, leiomyoma, breast cancer, and meningioma. The antiprogestin activity of RU-486 is mediated by binding to the PR (Wardell and Edwards, 2005). Binding of RU-486 induces a conformational change in the PR LBD that facilitates the dissociation from heat shock protein complexes, dimerization of the receptor, and cooperative binding to hormone response elements in target genes (Gass et al., 1998). The distinct conformational changes in the receptor LBD induced by RU-486 inhibit coactivator recruitment but facilitate receptor interaction with corepressors including nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid receptors (Wagner et al., 1998). RU-486 binding to PR also disrupts an intramolecular interaction between the N and C domains that has been shown to be required for maximal activity of the agonist-occupied receptor (Tetel et al., 1999). Detailed structure-function studies have also revealed that RU-486 binding may recruit RU-486-specific corepressors to specific residues in the receptor C-terminal tail (Vegeto et al., 1992; Xu et al., 1996). In addition, RU-486-bound receptors counteract agonist-bound receptors via formation of inactive heterodimers (Meyer et al., 1990; Leonhardt et al., 1998). Via these mechanisms, RU-486 acts as a potent antagonist for PR. RU-486 can also be a partial agonist for both PR and GR when selective coregulators are recruited (Jackson et al., 1997; Schulz et al., 2002). Other PR antagonists such as ZK 98299 have been developed. However, none of these compounds has been used extensively in the clinical setting because of toxicity.

Androgen therapy is primarily used in male hypogonadism, in aging, and in attempts to reverse protein loss after trauma, surgery, or prolonged immobilization (Katzung, 2004; Goodman et al., 2006). Androgens are also used in boys with delayed puberty, and the weak androgen danazol is used in women with endometriosis. The principal clinical application of AR antagonists such as flutamide, nilutamide, or bicalutamide is in the treatment of prostate cancer, usually in conjunction with long-acting luteinizing hormone-releasing hormone analogs. Androgen blockade usually decreases the volume of the primary and metastatic lesions by inducing apoptosis (Kyprianou et al., 1990). Despite the initial response to antiandrogen therapy, however, an androgen-refractory status with a fatal outcome frequently develops (Isaacs, 1999). Recurrent prostate cancer seems to result from increased AR signaling caused by increased AR expression in the presence or absence of AR gene amplifications (Koivisto et al., 1997), increased expression of enzymes that convert adrenal androgens to testosterone (Stanbrough et al., 2006), AR mutations (Tan et al., 1997; Taplin et al., 1999; Marcelli et al., 2000; Feldman and Feldman, 2001; Gregory et al., 2001), or AR activation in a ligand-independent manner (Craft et al., 1999). The onset of recurrent prostate cancer seems to involve increased AR-dependent growth factor signaling that overcomes apoptosis induced by androgen depletion (Ruijter et al., 1999; Feldman and Feldman, 2001). The aim of continued research in this area is to improve the prognosis for patients with prostate cancer.

Adverse effects of androgen treatment in women include hirsutism, acne, amenorrhea, clitoral enlargement, and deepening of the voice (Katzung, 2004; Goodman et al., 2006). Androgen replacement or performance-enhancing steroid use in men may cause sleep apnea, polycythemia, azoospermia, a decrease in testicular size, aggression, and psychosis. On the other hand, androgen blockade used in treating prostate cancer can be accompanied by hot flushes, loss of libido and sexual potency, and bone loss and osteoporosis (Labrie et al., 2004).

Prospectus

In 1849, Berthold showed that the transplantation of gonads into castrated roosters prevents the typical signs of castration and published the first experimental evidence for the effect of an endocrine gland (Klein, 1968). More than a century later, the first steroid receptor was cloned (Hollenberg et al., 1985). In the past 20 years, tremendous progress has been made in our understanding of the fundamental mechanisms of the intracellular steroid hormone receptors. Continued effort by researchers in the field is paving the way for more efficient and specific therapeutic approaches via modulation of the GR, MR, PR, and AR. Although each of these receptors is encoded by a single gene, recent evidence suggests that multiple GR, MR, and PR receptor isoforms are produced (Kastner et al., 1990; Pascual-Le Tallec et al., 2004; Lu and Cidlowski, 2005). Via both transcriptional and translational mechanisms, the GR gene, for instance, produces a minimum of 16 GR proteins with distinct functions and tissue distribution patterns (Lu and Cidlowski, 2005). These receptor isoforms increase the number of molecular targets underlying diseases. In addition, alternative signaling pathways of steroid hormone receptors are being investigated. The ability of the GR to change the half-lives of certain mRNAs, notably via interaction with specific signals in the untranslated regions, has been recognized as a potentially important anti-inflammatory mechanism (Mozo et al., 1998; Newton et al., 1998). Steroid receptors localized on cell membranes, such as the PR on spermatozoa, can also trigger multiple signaling pathways to affect cell function (Gadkar-Sable et al., 2005). Another important aspect of continuing research is the development of selective modulators of these receptors that are capable of maintaining the beneficial responses mediated by each receptor while reducing unwanted side effects (Chang and McDonnell, 2005). For example, an ideal selective GR modulator would have therapeutic actions in specific tissues or would have the ability to dissociate transactivation and transrepression effects of GR, an ideal selective PR modulator would have antiproliferative effects on the endometrium and breast but would not oppose the protective effects of estrogen on bones and the cardiovascular system (Smith and O'Malley, 2004; Chwalisz et al., 2005), and selective AR modulators could be effective therapies in treating prostate cancer. Thus, exciting new avenues are being discovered by studies of the classic steroid hormone receptors.

Tables 1, 2, 3, 4 summarize the functions, biologic activities, structural properties, and ligands of GR, MR, PR, and AR, respectively.

View this table:
  • View inline
  • View popup
TABLE 1

GR

View this table:
  • View inline
  • View popup
TABLE 2

MR

View this table:
  • View inline
  • View popup
TABLE 3

PR

View this table:
  • View inline
  • View popup
TABLE 4

AR

Footnotes

  • ↵1 Abbreviations: GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; DBD, DNA-binding domain; LBD, ligand-binding domain; GRE, glucocorticoid response element; AF, activation function; SRC-1, steroid receptor coactivator 1; ACTH, corticotropin; CBG, corticosteroid-binding globulin; CNS, central nervous system; SHBG, sex hormone-binding globulin; HSP, heat shock protein; NCoR, nuclear receptor corepressor.

  • Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

  • doi:10.1124/pr.58.4.9.

  • The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    Amasheh S, Epple HJ, Mankertz J, Detjen K, Goltz M, Schulzke JD, and Fromm M (2000) Differential regulation of ENaC by aldosterone in rat early and late distal colon. Ann NY Acad Sci 915: 92-94.
    OpenUrlPubMed
  2. ↵
    Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, and Evans RM (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science (Wash DC) 237: 268-275.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Auchus RJ (2004) The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab 15: 432-438.
    OpenUrlCrossRefPubMed
  4. ↵
    Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, and Schutz G (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci USA 95: 9424-9429.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Bevan CL, Hoare S, Claessens F, Heery DM, and Parker MG (1999) The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol 19: 8383-8392.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, et al. (2005) A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem 280: 31283-31293.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, et al. (2002) Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110: 93-105.
    OpenUrlCrossRefPubMed
  8. ↵
    Bray PJ and Cotton RG (2003) Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Hum Mutat 21: 557-568.
    OpenUrlCrossRefPubMed
  9. ↵
    Buttgereit F, Burmester GR, and Lipworth BJ (2005) Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet 365: 801-803.
    OpenUrlPubMed
  10. ↵
    Calle C, Campion J, Garcia-Arencibia M, Maestro B, and Davila N (2003) Transcriptional inhibition of the human insulin receptor gene by aldosterone. J Steroid Biochem Mol Biol 84: 543-553.
    OpenUrlCrossRefPubMed
  11. ↵
    Chang CS, Kokontis J, and Liao ST (1988) Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science (Wash DC) 240: 324-326.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Chang CY and McDonnell DP (2005) Androgen receptor-cofactor interactions as targets for new drug discovery. Trends Pharmacol Sci 26: 225-228.
    OpenUrlCrossRefPubMed
  13. ↵
    Chen S, Wang J, Yu G, Liu W, and Pearce D (1997) Androgen and glucocorticoid receptor heterodimer formation: a possible mechanism for mutual inhibition of transcriptional activity. J Biol Chem 272: 14087-14092.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, and Elger W (2005) Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 26: 423-438.
    OpenUrlCrossRefPubMed
  15. ↵
    Cidlowski JA, Bellingham DL, Powell-Oliver FE, Lubahn DB, and Sar M (1990) Novel antipeptide antibodies to the human glucocorticoid receptor: recognition of multiple receptor forms in vitro and distinct localization of cytoplasmic and nuclear receptors. Mol Endocrinol 4: 1427-1437.
    OpenUrlCrossRefPubMed
  16. ↵
    Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, and Schutz G (1995) Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9: 1608-1621.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Cole TJ, Myles K, Purton JF, Brereton PS, Solomon NM, Godfrey DI, and Funder JW (2001) GRKO mice express an aberrant dexamethasone-binding glucocorticoid receptor, but are profoundly glucocorticoid resistant. Mol Cell Endocrinol 173: 193-202.
    OpenUrlCrossRefPubMed
  18. ↵
    Craft N, Shostak Y, Carey M, and Sawyers CL (1999) A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5: 280-285.
    OpenUrlCrossRefPubMed
  19. ↵
    de Kloet ER, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, and de Jong W (2000) Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int 57: 1329-1336.
    OpenUrlCrossRefPubMed
  20. ↵
    Diamond MI, Miner JN, Yoshinaga SK, and Yamamoto KR (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science (Wash DC) 249: 1266-1272.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Drouin J, Sun YL, Chamberland M, Gauthier Y, De Lean A, Nemer M, and Schmidt TJ (1993) Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO (Eur Mol Biol Organ) J 12: 145-156.
    OpenUrlPubMed
  22. ↵
    Epple HJ, Amasheh S, Mankertz J, Goltz M, Schulzke JD, and Fromm M (2000) Early aldosterone effect in distal colon by transcriptional regulation of ENaC subunits. Am J Physiol 278: G718-G724.
    OpenUrl
  23. ↵
    Fagart J, Huyet J, Pinon GM, Rochel M, Mayer C, and Rafestin-Oblin ME (2005) Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension. Nat Struct Mol Biol 12: 554-555.
    OpenUrlCrossRefPubMed
  24. ↵
    Feldman BJ and Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34-45.
    OpenUrlCrossRefPubMed
  25. ↵
    Funder JW (1993) Mineralocorticoids, glucocorticoids, receptors and response elements. Science (Wash DC) 259: 1132-1133.
    OpenUrlFREE Full Text
  26. ↵
    Funder JW (2004) Is aldosterone bad for the heart? Trends Endocrinol Metab 15: 139-142.
    OpenUrlCrossRefPubMed
  27. ↵
    Gadkar-Sable S, Shah C, Rosario G, Sachdeva G, and Puri C (2005) Progesterone receptors: various forms and functions in reproductive tissues. Front Biosci 10: 2118-2130.
    OpenUrlPubMed
  28. ↵
    Gass EK, Leonhardt SA, Nordeen SK, and Edwards DP (1998) The antagonists RU486 and ZK98299 stimulate progesterone receptor binding to deoxyribonucleic acid in vitro and in vivo, but have distinct effects on receptor conformation. Endocrinology 139: 1905-1919.
    OpenUrlCrossRefPubMed
  29. ↵
    Goodman LS, Gilman A, Brunton LL, Lazo JS, and Parker KL (2006) Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York.
  30. ↵
    Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, and Wilson EM (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61: 4315-4319.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    He B, Gampe RT Jr, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, and Wilson EM (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16: 425-438.
    OpenUrlCrossRefPubMed
  32. ↵
    He B, Kemppainen JA, Voegel JJ, Gronemeyer H, and Wilson EM (1999) Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH2-terminal domain. J Biol Chem 274: 37219-37225.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    He B, Minges JT, Lee LW, and Wilson EM (2002) The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem 277: 10226-10235.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, and Evans RM (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature (Lond) 318: 635-641.
    OpenUrlCrossRefPubMed
  35. ↵
    Isaacs JT (1999) The biology of hormone refractory prostate cancer: why does it develop? Urol Clin North Am 26: 263-273.
    OpenUrlCrossRefPubMed
  36. ↵
    Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, and Horwitz KB (1997) The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 11: 693-705.
    OpenUrlCrossRefPubMed
  37. ↵
    Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, and Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO (Eur Mol Biol Organ) J 9: 1603-1614.
    OpenUrlPubMed
  38. ↵
    Katzung BG (2004) Basic and Clinical Pharmacology, McGraw-Hill, New York.
  39. ↵
    Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K, Engstrom O, Harlan J, Muchmore S, et al. (2003) The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem 278: 22748-22754.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Klein M (1968) Berthold's article: transplantation of the testes (1849). Arch Anat Histol Embryol 51: 379-386.
    OpenUrlPubMed
  41. ↵
    Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T, et al. (1997) Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 57: 314-319.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    Kolla V and Litwack G (2000) Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor. Mol Cell Biochem 204: 35-40.
    OpenUrlCrossRefPubMed
  43. ↵
    Kolla V, Robertson NM, and Litwack G (1999) Identification of a mineralocorticoid/glucocorticoid response element in the human Na/K ATPase α1 gene promoter. Biochem Biophys Res Commun 266: 5-14.
    OpenUrlCrossRefPubMed
  44. ↵
    Krozowski ZS and Funder JW (1983) Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA 80: 6056-6060.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Kyprianou N, English HF, and Isaacs JT (1990) Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation. Cancer Res 50: 3748-3753.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    Labrie F, Cusan L, Gomez J, Luu-The V, Candas B, Belanger A, and Labrie C (2004) Major impact of hormonal therapy in localized prostate cancer—death can already be an exception. J Steroid Biochem Mol Biol 92: 327-344.
    OpenUrlCrossRefPubMed
  47. ↵
    Langley E, Kemppainen JA, and Wilson EM (1998) Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity. J Biol Chem 273: 92-101.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Leonhardt SA, Altmann M, and Edwards DP (1998) Agonist and antagonists induce homodimerization and mixed ligand heterodimerization of human progesterone receptors in vivo by a mammalian two-hybrid assay. Mol Endocrinol 12: 1914-1930.
    OpenUrlCrossRefPubMed
  49. ↵
    Li Y, Suino K, Daugherty J, and Xu HE (2005) Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell 19: 367-380.
    OpenUrlCrossRefPubMed
  50. ↵
    Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, and Chang C (2005) Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes 54: 1717-1725.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    Lonard DM and O'Malley BW (2005) Expanding functional diversity of the coactivators. Trends Biochem Sci 30: 126-132.
    OpenUrlCrossRefPubMed
  52. ↵
    Lu NZ and Cidlowski JA (2005) Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 18: 331-342.
    OpenUrlCrossRefPubMed
  53. ↵
    Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, and Wilson EM (1988) Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science (Wash DC) 240: 327-330.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, and Sigler PB (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature (Lond) 352: 497-505.
    OpenUrlCrossRefPubMed
  55. ↵
    Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, and O'Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9: 2266-2278.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    Mangal RK, Wiehle RD, Poindexter AN 3rd, and Weigel NL (1997) Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol 63: 195-202.
    OpenUrlCrossRefPubMed
  57. ↵
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al. (1995) The nuclear receptor superfamily: the second decade. Cell 83: 835-839.
    OpenUrlCrossRefPubMed
  58. ↵
    Marcelli M, Ittmann M, Mariani S, Sutherland R, Nigam R, Murthy L, Zhao Y, DiConcini D, Puxeddu E, Esen A, et al. (2000) Androgen receptor mutations in prostate cancer. Cancer Res 60: 944-949.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, et al. (2000) Structural evidence for ligand specificity in the binding domain of the human androgen receptor: implications for pathogenic gene mutations. J Biol Chem 275: 26164-26171.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Matsumoto T, Takeyama K, Sato T, and Kato S (2005) Study of androgen receptor functions by genetic models. J Biochem (Tokyo) 138: 105-110.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Meyer ME, Pornon A, Ji JW, Bocquel MT, Chambon P, and Gronemeyer H (1990) Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor. EMBO (Eur Mol Biol Organ) J 9: 3923-3932.
    OpenUrlPubMed
  62. ↵
    Misrahi M, Atger M, d'Auriol L, Loosfelt H, Meriel C, Fridlansky F, Guiochon-Mantel A, Galibert F, and Milgrom E (1987) Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA. Biochem Biophys Res Commun 143: 740-748.
    OpenUrlCrossRefPubMed
  63. ↵
    Mozo L, Gayo A, Suarez A, Rivas D, Zamorano J, and Gutierrez C (1998) Glucocorticoids inhibit IL-4 and mitogen-induced IL-4Rα chain expression by different posttranscriptional mechanisms. J Allergy Clin Immunol 102: 968-976.
    OpenUrlCrossRefPubMed
  64. ↵
    Newton R, Seybold J, Kuitert LM, Bergmann M, and Barnes PJ (1998) Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA. J Biol Chem 273: 32312-32321.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Oakley RH, Sar M, and Cidlowski JA (1996) The human glucocorticoid receptor betaisoform: expression, biochemical properties, and putative function. J Biol Chem 271: 9550-9559.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Pascual-Le Tallec L, Demange C, and Lombes M (2004) Human mineralocorticoid receptor A and B protein forms produced by alternative translation sites display different transcriptional activities. Eur J Endocrinol 150: 585-590.
    OpenUrlAbstract
  67. ↵
    Poletti A (2004) The polyglutamine tract of androgen receptor: from functions to dysfunctions in motor neurons. Front Neuroendocrinol 25: 1-26.
    OpenUrlCrossRefPubMed
  68. ↵
    Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, and French FS (1995) Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16: 271-321.
    OpenUrlCrossRefPubMed
  69. ↵
    Rhen T and Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353: 1711-1723.
    OpenUrlCrossRefPubMed
  70. ↵
    Rogerson FM, Dimopoulos N, Sluka P, Chu S, Curtis AJ, and Fuller PJ (1999) Structural determinants of aldosterone binding selectivity in the mineralocorticoid receptor. J Biol Chem 274: 36305-36311.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Rogerson FM and Fuller PJ (2003) Interdomain interactions in the mineralocorticoid receptor. Mol Cell Endocrinol 200: 45-55.
    OpenUrlCrossRefPubMed
  72. ↵
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 288: 321-333.
    OpenUrlCrossRefPubMed
  73. ↵
    Ruijter E, van de Kaa C, Miller G, Ruiter D, Debruyne F, and Schalken J (1999) Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20: 22-45.
    OpenUrlCrossRefPubMed
  74. ↵
    Sartorato P, Cluzeaud F, Fagart J, Viengchareun S, Lombes M, and Zennaro MC (2004) New naturally occurring missense mutations of the human mineralocorticoid receptor disclose important residues involved in dynamic interactions with deoxyribonucleic acid, intracellular trafficking, and ligand binding. Mol Endocrinol 18: 2151-2165.
    OpenUrlCrossRefPubMed
  75. ↵
    Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, and Kato S (2003) Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochem Biophys Res Commun 300: 167-171.
    OpenUrlCrossRefPubMed
  76. ↵
    Schreiber C and Creinin M (2005) Mifepristone in abortion care. Semin Reprod Med 23: 82-91.
    OpenUrlCrossRefPubMed
  77. ↵
    Schulz M, Eggert M, Baniahmad A, Dostert A, Heinzel T, and Renkawitz R (2002) RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding. J Biol Chem 277: 26238-26243.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    Sica DA (2005) The risks and benefits of aldosterone antagonists. Curr Heart Fail Rep 2: 65-71.
    OpenUrlPubMed
  79. ↵
    Smith CL and O'Malley BW (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25: 45-71.
    OpenUrlCrossRefPubMed
  80. ↵
    Soyal SM, Mukherjee A, Lee KY, Li J, Li H, DeMayo FJ, and Lydon JP (2005) Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis 41: 58-66.
    OpenUrlCrossRefPubMed
  81. ↵
    Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, and Balk SP (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66: 2815-2825.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Tajima T, Kitagawa H, Yokoya S, Tachibana K, Adachi M, Nakae J, Suwa S, Katoh S, and Fujieda K (2000) A novel missense mutation of mineralocorticoid receptor gene in one Japanese family with a renal form of pseudohypoaldosteronism type 1. J Clin Endocrinol Metab 85: 4690-4694.
    OpenUrlCrossRefPubMed
  83. ↵
    Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M, Gumerlock PH, DeVere White RW, Pretlow TG, Harris SE, et al. (1997) Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 11: 450-459.
    OpenUrlCrossRefPubMed
  84. ↵
    Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, and Balk SP (1999) Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59: 2511-2515.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Tetel MJ, Giangrande PH, Leonhardt SA, McDonnell DP, and Edwards DP (1999) Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol Endocrinol 13: 910-924.
    OpenUrlCrossRefPubMed
  86. ↵
    Trapp T and Holsboer F (1996) Heterodimerization between mineralocorticoid and glucocorticoid receptors increases the functional diversity of corticosteroid action. Trends Pharmacol Sci 17: 145-149.
    OpenUrlCrossRefPubMed
  87. ↵
    Vegeto E, Allan GF, Schrader WT, Tsai MJ, McDonnell DP, and O'Malley BW (1992) The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 69: 703-713.
    OpenUrlCrossRefPubMed
  88. ↵
    Verrey F, Schaerer E, Zoerkler P, Paccolat MP, Geering K, Kraehenbuhl JP, and Rossier BC (1987) Regulation by aldosterone of Na+,K+-ATPase mRNAs, protein synthesis, and sodium transport in cultured kidney cells. J Cell Biol 104: 1231-1237.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Wagner BL, Norris JD, Knotts TA, Weigel NL, and McDonnell DP (1998) The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Biol 18: 1369-1378.
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Wardell SE and Edwards DP (2005) Mechanisms controlling agonist and antagonist potential of selective progesterone receptor modulators (SPRMs). Semin Reprod Med 23: 9-21.
    OpenUrlCrossRefPubMed
  91. ↵
    Williams SP and Sigler PB (1998) Atomic structure of progesterone complexed with its receptor. Nature (Lond) 393: 392-396.
    OpenUrlCrossRefPubMed
  92. ↵
    Xu J, Nawaz Z, Tsai SY, Tsai MJ, and O'Malley BW (1996) The extreme C terminus of progesterone receptor contains a transcriptional repressor domain that functions through a putative corepressor. Proc Natl Acad Sci USA 93: 12195-12199.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Pharmacological Reviews: 58 (4)
Pharmacological Reviews
Vol. 58, Issue 4
1 Dec 2006
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Pharmacological Reviews article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors
(Your Name) has forwarded a page to you from Pharmacological Reviews
(Your Name) thought you would be interested in this article in Pharmacological Reviews.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Nick Z. Lu, Suzanne E. Wardell, Kerry L. Burnstein, Donald Defranco, Peter J. Fuller, Vincent Giguere, Richard B. Hochberg, Lorraine McKay, Jack-Michel Renoir, Nancy L. Weigel, Elizabeth M. Wilson, Donald P. McDonnell and John A. Cidlowski
Pharmacological Reviews December 1, 2006, 58 (4) 782-797; DOI: https://doi.org/10.1124/pr.58.4.9

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Nick Z. Lu, Suzanne E. Wardell, Kerry L. Burnstein, Donald Defranco, Peter J. Fuller, Vincent Giguere, Richard B. Hochberg, Lorraine McKay, Jack-Michel Renoir, Nancy L. Weigel, Elizabeth M. Wilson, Donald P. McDonnell and John A. Cidlowski
Pharmacological Reviews December 1, 2006, 58 (4) 782-797; DOI: https://doi.org/10.1124/pr.58.4.9
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Introduction
    • Structure
    • Endogenous Ligands and Their Functions
    • Therapeutic Uses and Limitations
    • Prospectus
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • International Union of Pharmacology. LXVI. Orphan Nuclear Receptors
  • Foreword
Show more Special Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Pharmacological Reviews
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacology Research & Perspectives
ISSN 1521-0081 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics