Steroid Receptor Activation: The Glucocorticoid Receptor as a Model System

  • Gerald Litwack
  • Thomas J. Schmidt
  • Andrea Miller-Diener
  • Maria Webb
  • Peter Bodine
  • Carol A. Barnett
  • David Platt
  • Robert C. Baldridge
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 196)


The glucocorticoid receptor has been used as a model for steroid receptor activation. Because of recent evidence for the essentially nuclear location of the unoccupied receptors of 1,25-dihydroxycholecalciferol and 17 β-estradiol, the significance of the activation mechanism converting unactivated receptor complexes to DNA-binding forms is unclear for some receptors. Up to now the weight of evidence favors a cytoplasmic location of the unactivated glucocorticoid receptor. In this article we describe studies on the nature of the activation mechanism and of regulatory factors. Activation is defined as the conversion of non-DNA binding forms of steroid-receptor complexes to DNA binding forms. In vivo studies suggest that the activation mechanism has biological significance since it occurs under physiological conditions. The activation mechanism may consist of two steps in vitro, the first of which is sensitive to molybdate. The second step may involve the removal of an RNA from the receptor complex by RNase. Activation also results in a decreased molecular size of the receptor complex. Regulatory factors influencing activation which have been identified so far include a low molecular weight modulator which inhibits activation and a macromolecular inhibitor. A macromolecule in cytosol also acts as a stimulator of the second step of activation and may be RNase. Since phosphorylation/dephosphorylation may play some role in this overall process, the activity of a protein kinase has been described which is associated with the purified, liganded receptor and which mediates the phosphorylation of the 90,000 molecular weight steroid-binding component of the receptor complex. All of these observations are synthesized into a speculative mechanism of action of the glucocorticoid receptor complex and its activation.


Glucocorticoid Receptor Receptor Complex Triamcinolone Acetonide Estradiol Receptor Coid Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Walters, W. Hunziker, A. Norman, Unoccupied 1,25-dihydroxyvitamin D3 receptors. Nuclear/cytosol ratio depends on ionic strength. J. Biol. Chem. 255: 6799 (1980).PubMedGoogle Scholar
  2. 2.
    W. V. Welshons, M. E. Lieberman, J. Gorski, Nuclear localization of unoccupied oestrogen receptors. Nature 307: 747 (1984).PubMedCrossRefGoogle Scholar
  3. 3.
    W. J. King, G. L. Greene, Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 307: 745 (1984).PubMedCrossRefGoogle Scholar
  4. 4.
    P. L. Sheridan, J. M. Buchanan, V. C. Anselmo, P. M. Martin, Equilibrium: the intracellular distribution of steroid receptors. Nature 282: 579 (1979).PubMedCrossRefGoogle Scholar
  5. 5.
    A. C. Abbott, C. C. Bird, Conformation of two-step model of glucocorticoid hormone action in a glucocorticoid-sensitive human lymphoid cell line. Biochem. Biophys. Res. Commun. 106: 1056 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    J. D. Baxter, G. G. Rousseau, M. C. Benson, R. L. Garcea, J. Ito, G. M. Tomkins, Role of DNA and specific cytoplasmic receptors in glucocorticoid action. Proc. Nat. Acad. Sci. 69: 1892 (1972).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Kalimi, M. Beato, P. Feigelson, Interaction of glucocorticoids with rat liver nuclei. I. Role of the cytosol proteins. Biochemistry 12: 3365 (1973).PubMedCrossRefGoogle Scholar
  8. 8.
    G. Litwack, R. Filler, S. A. Rosenfield, N. Lichtash, C. A. Wishman, S. Singer, Liver cytosol corticosteroid binder II, a hormone receptor. J. Biol. Chem. 248: 7481 (1973).PubMedGoogle Scholar
  9. 9.
    E. Milgrom, M. Atger, E-E Baulieu, Acidophilic activation of steroid hormone receptors. Biochemistry 12: 5198 (1973).PubMedCrossRefGoogle Scholar
  10. 10.
    E. V. Jensen, T. Suzuki, T. Kawashima, W. E. Stumpf, P. W. Jungblut, E. R. DeSombre, A two-step mechanism for the interaction of estradiol with rat uterus. Proc. Nat. Acad. Sci. 59: 632 (1968).PubMedCrossRefGoogle Scholar
  11. 11.
    T. J. Schmidt, G. Litwack, Activation of the glucocorticoidreceptor complex. Physiol. Revs. 62: 1131 (1982).Google Scholar
  12. 12.
    A. Munck, R. Foley, Activation of steroid hormone-receptor complexes in intact target cells in physiological conditions. Nature 278: 752 (1980).CrossRefGoogle Scholar
  13. 13.
    Y. Sakaue, E. B. Thompson, Characterization of two forms of glucocorticoid hormone-receptor complex separated by DEAEcellulose column chromatography. Biochem. Biophys. Res. Commun. 77: 533 (1977).PubMedCrossRefGoogle Scholar
  14. 14.
    R. D. Markovic, G. Litwack, Activation mechanism of glucocorticoid receptor proceeds in vivo. Arch. Biochem. Biophys. 202: 374 (1980).PubMedCrossRefGoogle Scholar
  15. 15.
    L. G. Parchman, G. Litwack, Resolution of activated and unactivated forms of the glucocorticoid receptor from rat liver. Arch. Biochem. Biophys. 183: 374 (1977).PubMedCrossRefGoogle Scholar
  16. 16.
    P. Grandics, A. Miller, T. J. Schmidt, D. Mittman, Litwack G, Purification of unactivated glucocorticoid receptor to apparent homogeneity and studies on the activation mechanism. J. Biol. Chem. 259: 3173 (1984).PubMedGoogle Scholar
  17. 17.
    P. Grandics, A. Miller, T. J. Schmidt, G. Litwack, Phosphorylation in vivo of rat hepatic glucocorticoid receptor. Biochem. Biophys. Res. Commun. 120: 59 (1984).PubMedCrossRefGoogle Scholar
  18. 18.
    P. R. Housley, W. B. Pratt, Small 32P-labeled components of L cells that coelute with the molybdate-stabilized glucocorticoid receptor during purification. Fed. Proc. 43: 1572 (1984).Google Scholar
  19. 19.
    T. J. Schmidt, A. Miller, M. L. Webb, P. Grandics, G. Litwack, Thermal activation of purified rat hepatic glucocorticoidreceptor complexes-possibly a two-step mechanism. Proc 7th Intern Congr Endocrinol (Quebec City) Excerpta Medica, Amsterdam-Oxford-Princeton, p. 1619 (1984)Google Scholar
  20. 20.
    S. Liao, S. Smythe, J. L. Tymoczko, G. P. Rossini, R. A. Hipakka, RNA-dependent release of androgen and other steroid-receptor complexes from DNA. J. Biol. Chem. 255: 5545 (1980).Google Scholar
  21. 21.
    T. W. Hutchens, F. S. Markland, E. F. Hawkins, RNA induced reversal of glucocorticoid receptor activation. Biochem. Biophys. Res. Commun. 105: 20 (1982).PubMedCrossRefGoogle Scholar
  22. 22.
    M. H. Cake, J. A. Goidl, L. G. Parchman, G. Litwack, Involvement of a low molecular weight component(s) in the mechanism of action of the glucocorticoid receptor. Biochem. Biophys. Res. Commun. 71: 45 (1976).PubMedCrossRefGoogle Scholar
  23. 23.
    C. A. Barnett, T. J. Schmidt, G. Litwack, The effects of calf intestinal alkaline phosphatase, phosphatase inhibitors and phosphorylated compounds on the rate of activation of glucocorticoid-receptor complexes. Biochemistry 19: 5446 (1980).PubMedCrossRefGoogle Scholar
  24. 24.
    J. A. Goidl, M. H. Cake, K. P. Dolan, L. G. Parchman, G. Litwack, Activation of the glucocorticoid receptor complex. Biochemistry 16: 2125 (1977).PubMedCrossRefGoogle Scholar
  25. 25.
    A. S. Miller, T. J. Schmidt, G. Litwack, Protein kinase activity of putified rat hepatic glucocorticoid receptor. Proc 7th Intern Congr Endocrinol (Quebec City) Excerpta Medica, Amsterdam-Oxford-Princeton, p. 788 (1984).Google Scholar
  26. 26.
    T. J. Schmidt, A. Miller-Diener, G. Litwack, -Lapachone, a specific competitive inhibitor or ligand binding to the glucocorticoid receptor. J. Biol. Chem. 259: 9536 (1984).PubMedGoogle Scholar
  27. 27.
    M. H. Cake, D. M. DiSorbo, G. Litwack, Effect of pyridoxal phosphate on the DNA binding site of the activated hepatic glucocorticoid receptor. J. Biol. Chem. 253: 4886 (1978).PubMedGoogle Scholar
  28. 28.
    J. L. Tymoczko, M. M. Phillips, S. M. Vernon, Binding of the rat liver 7–8S dexamethaseone receptor to deoxyribonucleic acid. Arch. Biochem. Biophys. 230: 345 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    S. B. Eastman-Reks, C. E. Reker, W. V. Vedeckis, Structure and subunit dissociation of the mouse glucocorticoid receptor: rapid analysis using vertical tube rotor sucrose gradients. Arch. Biochem. Biophys. 230: 274 (1984).PubMedCrossRefGoogle Scholar
  30. 30.
    W. V. Vedeckis, C. E. Reker, Alkaline phosphatase promotion of the 9.1S to 5.2S transformation of the mouse glucocorticoid receptor. Proc 7th Intern Congr Endocrinol (Quebec City) Excerpta Medica, Amsterdam-Oxford-Princeton, p. 1620 (1984).Google Scholar
  31. 31.
    D. M. DiSorbo, D. S. Phelps, G. Litwack, Probes of basic amino acid residues affect active sites of the glucocorticoid receptor. Endocrinology 106: 922 (1980).PubMedCrossRefGoogle Scholar
  32. 32.
    B. Groner, N. Kennedy, P. Skroch, N. E. Hymes, H. Ponta, DNA sequences involved in the regulation of gene expression by glucocorticoid hormones. Biochim. Biophys. Acta. 781: 1 (1984).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Gerald Litwack
    • 1
  • Thomas J. Schmidt
    • 1
  • Andrea Miller-Diener
    • 1
  • Maria Webb
    • 1
    • 2
  • Peter Bodine
    • 1
  • Carol A. Barnett
    • 1
    • 3
  • David Platt
    • 1
  • Robert C. Baldridge
    • 1
    • 4
  1. 1.Fels Research InstituteTemple University School of MedicinePhiladelphiaUSA
  2. 2.Department of BiochemistryTemple University School of MedicineUSA
  3. 3.Department of BiologySan Diego State UniversitySan DiegoUSA
  4. 4.Department of BiochemistryJefferson Medical College, Thomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations