Skip to main content
SpringerLink
Log in

Cytosolic Glucocorticoid Receptor-Interacting Proteins

  • Conference paper
Book cover Recent Advances in Glucocorticoid Receptor Action

Part of the book series: Ernst Schering Research Foundation Workshop ((SCHERING FOUND,volume 40))

Abstract

The classic view of glucocorticoid mechanism of action involves the concept of a non-liganded receptor residing in the cytoplasm of cells. The receptor is maintained in an inactive state, with regard to the ability to bind to DNA, by the interaction with a multi-protein chaperone complex that contains, among other proteins, a dimer of hsp90, hsp70, hsp40, FKBP52 and p23. Of these proteins, hsp90 has been shown to maintain glucocorticoid receptor (GR) in a conformation optimal for ligand binding, and it also serves to cover the two nuclear localization signals (NL) of GR. NL1 is mapped to certain basic amino acid sequences in the DNA-binding domain and hinge region, and NL2 is broadly mapped to the ligand-binding domain of GR. Upon ligand binding, GR dissociates from hsp90 and also from several of the other chaperone proteins, and translocates to the nucleus. In the nucleus, GR is present as a homodimer and acts as a ligand-dependent transcription factor binding specific DNA sequences, i.e., glucocorticoid response elements (GRE) of glucocorticoid-regulated genes. In this process, GR can associate with adaptor proteins and the basal transcription machinery, as well as with specific transcription factors and coregulators. The classical view of GR mechanism of action has been shown to be even more complex, and GR action most likely encompasses more protein interactions than described above.

Proposed model of GR action. Glucocorticoids bind intracellular glucocorticoid receptors (GR). Upon binding and activation, GR dissociate from some of the heat-shock proteins in the GR protein multi-complex, but also probably recruit new interaction partners and enter the nucleus. Not all of the receptor-associating proteins are identified and fully characterized. In the nucleus, GR also bind to adaptor proteins and coregulators

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aittomaki S, Pesu M, Groner B, Janne OA, Palvimo JJ, Silvennoinen 0 (2000) Cooperation among Statl, glucocorticoid receptor, and PU.1 in transcriptional activation of the high-affinity Fc gamma receptor I in monocytes. J Immunol 164: 5689–5697

    CAS  Google Scholar 

  • Akner G, Sundqvist KG, Denis M, Wikstrom AC, Gustafsson JA (1990) Immunocytochemical localization of glucocorticoid receptor in human gingival fibroblasts and evidence for a colocalization of glucocorticoid receptor with cytoplasmic microtubules. Eur J Cell Biol 53: 390–401

    PubMed  CAS  Google Scholar 

  • Akner G, Mossberg K, Wikstrom AC, Sundqvist KG, Gustafsson JA (1991) Evidence for colocalization of glucocorticoid receptor with cytoplasmic microtubules in human gingival fibroblasts, using two different monoclonal anti-GR antibodies, confocal laser scanning microscopy and image analysis. J Steroid Biochem Mol Biol 39: 419–432

    Article  PubMed  CAS  Google Scholar 

  • Aljada A, Ghanim H, Assian E, Mohanty P, Hamouda W, Garg R, Dandona P (1999) Increased IkappaB expression and diminished nuclear NF-kappaB in human mononuclear cells following hydrocortisone injection. J Clin Endocrinol Metab 84: 3386–3389

    Article  PubMed  CAS  Google Scholar 

  • Amici C, Belardo G, Rossi A, Santoro MG (2001) Activation of I kappa b kinase by herpes simplex virus type 1. A novel target for anti-herpetic therapy. J Biol Chem 276: 28759–28766

    Google Scholar 

  • Awan AR, Harmenberg J, Flink O, Field HJ (1998) Combinations of antiviral and anti-inflammatory preparations for the topical treatment of herpes simplex virus assessed using a murine zosteriform infection model. Antivir Chem Chemother 9: 19–24

    PubMed  CAS  Google Scholar 

  • Bagatell R, Khan O, Paine-Murrieta G, Taylor CW, Akinaga S, Whitesell L (2001) Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer. Clin Cancer Res 7: 2076–2084

    PubMed  CAS  Google Scholar 

  • Bonk T, Humeny A (2001) MALDI-TOF-MS analysis of protein and DNA. Neuroscientist 7: 6–12

    Article  PubMed  CAS  Google Scholar 

  • Caldenhoven E, Liden J, Wissink S, Van de Stolpe A, Raaijmakers J, Koenderman L, Okret S, Gustafsson JA, Van der Saag PT (1995) Negative cross-talk between Re1A and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. Mol Endocrinol 9: 401–412

    Article  PubMed  CAS  Google Scholar 

  • Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ (1998) Increasing complexity of Ras signaling. Oncogene 17: 1395–1413

    Article  PubMed  CAS  Google Scholar 

  • Cella N, Groner B, Hynes NE (1998) Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocorticoid receptor in mammary cells. Mol Cell Biol 18: 1783–1792

    PubMed  CAS  Google Scholar 

  • Cheung J, Smith DF (2000) Molecular chaperone interactions with steroid receptors: an update. Mol Endocrinol 14: 939–946

    Article  PubMed  CAS  Google Scholar 

  • Choi I, Ko C, Park-Sarge OK, Nie R, Hess RA, Graves C, Katzenellenbogen BS (2001) Human estrogen receptor beta-specific monoclonal antibodies: characterization and use in studies of estrogen receptor beta protein expression in reproductive tissues. Mol Cell Endocrinol 181: 139–150

    Article  PubMed  CAS  Google Scholar 

  • Croxtall JD, Choudhury Q, Flower RJ (2000) Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol 130: 289–298

    Article  PubMed  CAS  Google Scholar 

  • De Bosscher K, Vanden Berghe W, Vermeulen L, Plaisance S, Boone E, Haegeman G (2000) Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci U S A 97: 3919–3924

    Article  PubMed  Google Scholar 

  • Deroo BJ, Archer TK (2001) Glucocorticoid receptor-mediated chromatin remodeling in vivo. Oncogene 20: 3039–3046

    Article  PubMed  CAS  Google Scholar 

  • Dong Y, Poellinger L, Gustafsson JA, Okret S (1988) Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. Mol Endocrinol 2: 1256–1264

    Article  PubMed  CAS  Google Scholar 

  • Doucas V, Shi Y, Miyamoto S, West A, Verma I, Evans RM (2000) Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci U S A 97: 11893–11898

    Article  PubMed  CAS  Google Scholar 

  • Dreyer LL, Sydiskis RJ, Bashirelahi N (1989) Effect of dexamethasone on herpes simplex virus replication in mouse neuroblastoma cells (NB41A3): receptor characteristics. J Clin Lab Anal 3: 236–243

    Article  PubMed  CAS  Google Scholar 

  • Espinas ML, Roux J, Ghysdael J, Pictet R, Grange T (1994) Participation of Ets transcription factors in the glucocorticoid response of the rat tyrosine aminotransferase gene. Mol Cell Biol 14: 4116–4125

    PubMed  CAS  Google Scholar 

  • Evans-Storms RB, Cidlowski JA (2000) Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: the role of nuclear factor-kappaB. Endocrinology 141: 1854–1862

    Article  PubMed  CAS  Google Scholar 

  • Fantl WJ, Muslin AJ, Kikuchi A, Martin JA, MacNicol AM, Gross RW, Williams LT (1994) Activation of Raf–1 by 14–3–3 proteins. Nature 371: 612 – 614

    Article  PubMed  CAS  Google Scholar 

  • Galigniana MD, Radanyi C, Renoir JM, Housley PR, Pratt WB (2001) Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus. J Biol Chem 276: 14884–14889

    Article  PubMed  CAS  Google Scholar 

  • Harrell AJ, Sydiskis RH (1982) The effect of dexamethasone on the replication of herpes simplex virus in human gingival fibroblast cultures. J Baltimore Coll Dent Surg 35: 9–13

    PubMed  CAS  Google Scholar 

  • Hiroi H, Inoue S, Watanabe T, Goto W, Orimo A, Momoeda M, Tsutsumi O, Taketani Y, Muramatsu M (1999) Differential immunolocalization of estrogen receptor alpha and beta in rat ovary and uterus. J Mol Endocrinol 22: 37–44

    Article  PubMed  CAS  Google Scholar 

  • Htun H, Barsony J, Renyi I, Gould DL, Hager GL (1996) Visualization of glucocorticoid receptor translocation and intranuclear organization in living cells with a green fluorescent protein chimera. Proc Natl Acad Sci USA 93: 4845–4850

    Article  PubMed  CAS  Google Scholar 

  • Irie K, Gotoh Y, Yashar BM, Errede B, Nishida E, Matsumoto K (1994) Stimulatory effects of yeast and mammalian 14–3–3 proteins on the Raf protein kinase. Science 265: 1716 – 1719

    Article  PubMed  CAS  Google Scholar 

  • Karin M, Chang L (2001) AP-1-glucocorticoid receptor crosstalk taken to a higher level. J Endocrinol 169: 447–451

    Article  PubMed  CAS  Google Scholar 

  • King KL, Cidlowski JA (1998) Cell cycle regulation and apoptosis. Annu Rev Physiol 60: 601–617

    Article  PubMed  CAS  Google Scholar 

  • Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN, Chrousos GP (1999) The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J Exp Med 189: 51–62

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Kume A, Li M, Doyu M, Hata M, Ohtsuka K, Sobue G (2000) Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem 275: 8772–8778

    Article  PubMed  CAS  Google Scholar 

  • Liden J, Delaunay F, Rafter I, Gustafsson J, Okret S (1997) A new function for the C-terminal zinc finger of the glucocorticoid receptor. Repression of RelA transactivation. J Biol Chem 272: 21467–1472

    Google Scholar 

  • Liden J, Rafter I, Truss M, Gustafsson JA, Okret S (2000) Glucocorticoid effects on NF-kappaB binding in the transcription of the ICAM-1 gene. Biochem Biophys Res Commun 273: 1008–1014

    Article  PubMed  CAS  Google Scholar 

  • Lim CS, Baumann CT, Htun H, Xian W, Irie M, Smith CL, Hager GL (1999) Differential localization and activity of the A- and B-forms of the human progesterone receptor using green fluorescent protein chimeras. Mol Endocrinol 13: 366–375

    Article  PubMed  CAS  Google Scholar 

  • Liu J, DeFranco DB (2000) Protracted nuclear export of glucocorticoid receptor limits its turnover and does not require the exportin 1/CRM1-directed nuclear export pathway. Mol Endocrinol 14: 40–51

    Article  PubMed  Google Scholar 

  • McKay LI, Cidlowski JA (1998) Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol Endocrinol 12: 45–56

    Article  PubMed  CAS  Google Scholar 

  • McNally JG, Muller WG, Walker D, Wolford R, Hager GL (2000) The glucocorticoid receptor: rapid exchange with regulatory sites in living cells. Science 287: 1262–1265

    Article  PubMed  CAS  Google Scholar 

  • Miyata Y, Yahara I (1991) Cytoplasmic 8S glucocorticoid receptor binds to actin filaments through the 90-kDa heat shock protein moiety. J Biol Chem 266: 8779–8783

    PubMed  CAS  Google Scholar 

  • Nissen RM, Yamamoto KR (2000) The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 14: 2314–2329

    Article  PubMed  CAS  Google Scholar 

  • Notter MF, Docherty JJ (1978) Steroid hormone alteration of herpes simplex virus type 1 replication. J Med Virol 2: 247–252

    Article  PubMed  CAS  Google Scholar 

  • Oakley RH, Sar M, Cidlowski JA (1996) The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 271: 9550–9559

    Google Scholar 

  • Oakley RH, Webster JC, Sar M, Parker CR, Jr., Cidlowski JA (1997) Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor. Endocrinology 138: 5028–5038

    Article  PubMed  CAS  Google Scholar 

  • Patel A, Hanson J, McLean TI, Olgiate J, Hilton M, Miller WE, Bachenheimer SL (1998) Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication. Virology 247: 212–222

    Article  PubMed  CAS  Google Scholar 

  • Perrot-Applanat M, Logeat F, Groyer-Picard MT, Milgrom E (1985) Immunocytochemical study of mammalian progesterone receptor using monoclonal antibodies. Endocrinology 116: 1473–1484

    Article  PubMed  CAS  Google Scholar 

  • Perrot-Applanat M, Lescop P, Milgrom E (1992) The cytoskeleton and the cellular traffic of the progesterone receptor. J Cell Biol 119: 337–348

    Article  PubMed  CAS  Google Scholar 

  • Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18: 306–360

    Article  PubMed  CAS  Google Scholar 

  • Pratt WB, Sanchez ER, Bresnick EH, Meshinchi S, Scherrer LC, Dalman FC, Welsh MJ (1989) Interaction of the glucocorticoid receptor with the Mr 90,000 heat shock protein: an evolving model of ligand-mediated receptor transformation and translocation. Cancer Res 49: 2222s - 2229s

    PubMed  CAS  Google Scholar 

  • Pratt WB, Silverstein AM, Galigniana MD (1999) A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37. Cell Signal 11: 839–851

    Article  PubMed  CAS  Google Scholar 

  • Qi M, Hamilton BJ, DeFranco D (1989) v-mos oncoproteins affect the nuclear retention and reutilization of glucocorticoid receptors. Mol Endocrinol 3: 1279–1288

    Google Scholar 

  • Ray A, Prefontaine KE (1994) Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci U S A 91: 752–756

    Article  PubMed  CAS  Google Scholar 

  • Refaeli Y, Levy DN, Weiner DB (1995) The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc Natl Acad Sci USA 92: 3621–3625

    Article  PubMed  CAS  Google Scholar 

  • Rong BL, Libermann TA, Kogawa K, Ghosh S, Cao LX, Pavan-Langston D, Dunkel EC (1992) HSV-1-inducible proteins bind to NF-kappa B-like sites in the HSV-1 genome. Virology 189: 750–756

    Article  PubMed  CAS  Google Scholar 

  • Roy S, McPherson RA, Apollon A, Yan J, Lane A, Clyde–Smith J, Hancock JF (1998) 14–3–3 facilitates Ras–dependent Raf–1 activation in vitro and in vivo. Mol Cell Biol 18: 3947 – 3955

    Google Scholar 

  • Savory JG, Hsu B, Laquian IR, Giffin W, Reich T, Hache RI, Lefebvre YA (1999) Discrimination between NL1- and NL2-mediated nuclear localization of the glucocorticoid receptor. Mol Cell Biol 19: 1025–1037

    PubMed  CAS  Google Scholar 

  • Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS Jr (1995) Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol 15: 943–953

    PubMed  CAS  Google Scholar 

  • Sheppard KA, Phelps KM, Williams AJ, Thanos D, Glass CK, Rosenfeld MG, Gerritsen ME, Collins T (1998) Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1. J Biol Chem 273: 29291–29294

    Article  PubMed  CAS  Google Scholar 

  • Shughrue Pi, Merchenthaler I (2001) Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol 436: 64–81

    Article  PubMed  CAS  Google Scholar 

  • Suen KL, Bustelo XR, Barbacid M (1995) Lack of evidence for the activation of the Ras/Raf mitogenic pathway by 14–3–3 proteins in mammalian cells. Oncogene 11: 825 – 831

    PubMed  CAS  Google Scholar 

  • Wakui H, Wright AP, Gustafsson J, Zilliacus J (1997) Interaction of the ligand–activated glucocorticoid receptor with the 14–3–3 eta protein. J Biol Chem 272: 8153 – 8156

    Article  PubMed  CAS  Google Scholar 

  • Wan Y, Coxe KK, Thackray VG, Housley PR, Nordeen SK (2001) Separable features of the ligand-binding domain determine the differential subcellular localization and ligand-binding specificity of glucocorticoid receptor and progesterone receptor. Mol Endocrinol 15: 17–31

    Article  PubMed  CAS  Google Scholar 

  • Widén C, Zilliacus J, Gustafsson JA, Wikstrom AC (2000) Glucocorticoid receptor interaction with 14–3–3 and Raf–1, a proposed mechanism for crosstalk of two signal transduction pathways. J Biol Chem 275: 39296 – 39301

    Article  PubMed  Google Scholar 

  • Wyszomierski SL, Yeh J, Rosen JM (1999) Glucocorticoid receptor/signal transducer and activator of transcription 5 (STAT5) interactions enhance STAT5 activation by prolonging STAT5 DNA binding and tyrosine phosphorylation. Mol Endocrinol 13: 330–343

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. A.-C. Wikström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Widén
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Erlandsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Hedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Zilliacus
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, P.O. Box 3640, 76021, Karlsruhe, Germany

    A. C. B. Cato

  2. Research Business Area Dermatology, Schering AG, Müllerstr. 178, 13342, Berlin, Germany

    H. Schäcke  & K. Asadullah  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Wikström, AC., Widén, C., Erlandsson, A., Hedman, E., Zilliacus, J. (2002). Cytosolic Glucocorticoid Receptor-Interacting Proteins. In: Cato, A.C.B., Schäcke, H., Asadullah, K. (eds) Recent Advances in Glucocorticoid Receptor Action. Ernst Schering Research Foundation Workshop, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04660-9_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-04660-9_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-04662-3

  • Online ISBN: 978-3-662-04660-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation