DNA-Dependent Cofactor Selectivity of the Glucocorticoid Receptor

  • A. Dostert
  • T. Heinzel
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 40)

Abstract

The glucocorticoid receptor (GR) is one of the best-characterized steroid receptors and essential for the regulation of multiple physiological processes. Due to their multiple inhibitory effects on the immune system, glucocorticoids are especially suited for treatment of inflammations and autoimmune diseases, but prolonged therapy results in severe metabolic side effects due to alterations in glucose and lipid metabolism. Further side effects include osteoporosis, atrophy of the skin, myopathy, and psychosis. In the absence of its ligand, the GR is localized in the cytoplasm as part of a multiprotein complex composed of GR, heat-shock proteins, and immunophilins. Binding of glucocorticoids to the receptor induces release of GR from this complex and subsequent translocation to the nucleus. This leads to binding of receptor dimers to specific DNA motifs in the regulatory regions of target genes and to activation of their transcription (Beato et al. 1995; Mangelsdorf et al. 1995). The function of dimeric receptors is also influenced considerably by neighboring transcription factors (Leers et al. 1994; Burcin et al. 1997). The GR shows further types of action, which do not require the binding of receptor dimers to DNA-recognition sequences (Heck et al. 1994; Reichardt et al. 1998). Binding of the ligand to the receptor leads in most of these cases to repressed activity of genes which are activated through other transcription factors, for example during the immunogenic reaction. This transcriptional crosstalk with transcription factors like AP-1, NF-κB or Stat5 occurs without direct binding to DNA; presumably on the basis of protein-protein interactions with the DNA-bound transcription factors (Jonat et al. 1990; Lucibello et al. 1990; Yang-Yen et al. 1990; Schüle and Evans 1991; König et al. 1992; Stöcklin et al. 1996; Heck et al. 1997). In another crosstalk mechanism (the proliferin gene), the GR presumably binds as a monomer along with other transcription factors to a “half” recognition sequence in a “composite element” (Diamond et al. 1990). Furthermore, negative response elements (nGREs; nTREs) have been described for glucocorticoid and also thyroid hormone receptors (Drouin et al. 1993; Saatcioglu et al. 1994; Lefstin and Yamamoto 1998; Awad et al. 1999). The molecular mechanism of all of these forms of gene repression via GR remains unclear.

Keywords

Estrogen Osteoporosis Adenosine Immobilization Dexamethasone 

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References

  1. Alland L, Muhle R, Hou H Jr, Potes J, Chin L, Schreiber-Agus N, DePinho RA (1997) Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387: 49–55PubMedCrossRefGoogle Scholar
  2. Awad TA, Bigler J, Ulmer JE, Hu YJ, Moore JM, Lutz M, Neiman PE, Collins SJ, Renkawitz R, Lobanenkov VV, Filippova GN (1999) Negative transcriptional regulation mediated by thyroid hormone response element 144 requires binding of the multivalent factor CTCF to a novel target DNA sequence. J Biol Chem 274: 27092–27098PubMedCrossRefGoogle Scholar
  3. Baniahmad A, Kohne AC, Renkawitz R (1992) A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor. EMBO J 11: 1015–1023PubMedGoogle Scholar
  4. Baniahmad A, Leng X, Burris TP, Tsai SY, Tsai MJ, O’Malley BW (1995) The tau 4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing. Mol Cell Biol 15: 76–86PubMedGoogle Scholar
  5. Baniahmad A, Thormeyer D, Renkawitz R (1997) tau4/tau c/AF-2 of the thyroid hormone receptor relieves silencing of the retinoic acid receptor silencer core independent of both tau4 activation function and full dissociation of corepressors. Mol Cell Biol 17: 4259–4271Google Scholar
  6. Beato M, Chalepakis G, Schauer M, Slater EP (1989) DNA regulatory elements for steroid hormones. J Steroid Biochem 32: 737–747PubMedCrossRefGoogle Scholar
  7. Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83: 851–857PubMedCrossRefGoogle Scholar
  8. Burcin M, Arnold R, Lutz M, Kaiser B, Runge D, Lottspeich F, Filippova GN, Lobanenkov VV, Renkawitz R (1997) Negative protein 1, which is required for function of the chicken lysozyme gene silencer in conjunction with hormone receptors, is identical to the multivalent zinc finger repressor CTCF. Mol Cell Biol 17: 1281–1288PubMedGoogle Scholar
  9. Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM (1996) Role of CBP/P300 in nuclear receptor signalling. Nature 383: 99–103PubMedCrossRefGoogle Scholar
  10. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377: 454–457PubMedCrossRefGoogle Scholar
  11. Chen H, Lin RJ, Schultz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569–580PubMedCrossRefGoogle Scholar
  12. Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249: 1266–1272PubMedCrossRefGoogle Scholar
  13. Dressel U, Thormeyer D, Altincicek B, Paululat A, Eggert M, Schneider S, Tenbaum SP, Renkawitz R, Baniahmad A (1999) Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily. Mol Cell Biol 19: 3383–3394PubMedGoogle Scholar
  14. Drouin J, Trifiro MA, Plante RK, Nemer M, Eriksson P, Wrange O (1989) Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. Mol Cell Biol 9: 5305–5314PubMedGoogle Scholar
  15. Drouin J, Sun YL, Chamberland M, Gauthier Y, De Lean A, Nemer M, Schmidt TJ (1993) Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J 12: 145–156PubMedGoogle Scholar
  16. Glass CK, Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14: 121–141PubMedGoogle Scholar
  17. Glass CK, Holloway JM, Devary OV, Rosenfeld MG (1988) The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell 54: 313–323PubMedCrossRefGoogle Scholar
  18. Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69: 990–1047PubMedGoogle Scholar
  19. Heck S, Kullmann M, Gast A, Ponta H, Rahmsdorf HJ, Herrlich P, Cato AC (1994) A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO J 13: 4087–4095PubMedGoogle Scholar
  20. Heck S, Bender K, Kullmann M, Gottlicher M, Herrlich P, Cato AC (1997) I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor. EMBO J 16: 4698–4707PubMedCrossRefGoogle Scholar
  21. Heery DM, Kalkhoven E, Hoare S, Parker MG (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387: 733–736PubMedCrossRefGoogle Scholar
  22. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG (1997) A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387: 43–48PubMedCrossRefGoogle Scholar
  23. Hörlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, et al. (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377: 397–404PubMedCrossRefGoogle Scholar
  24. Hu X, Lazar MA (1999) The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402: 93–96PubMedCrossRefGoogle Scholar
  25. Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P (1990) Antitumor promotion and antiinflammation: down-modulation of AP-1 ( Fos/Jun) activity by glucocorticoid hormone. Cell 62: 1189–1204Google Scholar
  26. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85: 403–414PubMedCrossRefGoogle Scholar
  27. König H, Ponta H, Rahmsdorf HJ, Herrlich P (1992) Interference between pathway-specific transcription factors: glucocorticoids antagonize phorbol ester-induced AP-1 activity without altering AP-1 site occupation in vivo. EMBO J 11: 2241–2246PubMedGoogle Scholar
  28. Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK (1995) Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377: 451–454PubMedCrossRefGoogle Scholar
  29. Leers J, Steiner C, Renkawitz R, Muller M (1994) A thyroid hormone receptor-dependent glucocorticoid induction. Mol Endocrinol 8: 440–447PubMedCrossRefGoogle Scholar
  30. Lefstin JA, Yamamoto KR (1998) Allosteric effects of DNA on transcriptional regulators. Nature 392: 885–888PubMedCrossRefGoogle Scholar
  31. Lucibello FC, Slater EP, Jooss KU, Beato M, Muller R (1990) Mutual transrepression of Fos and the glucocorticoid receptor: involvement of a functional domain in Fos which is absent in FosB. EMBO J 9: 2827–2834PubMedGoogle Scholar
  32. 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: 835–839PubMedCrossRefGoogle Scholar
  33. Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10: 384–391PubMedCrossRefGoogle Scholar
  34. Morrison NA, Shine J, Fragonas JC, Verkest V, McMenemy ML, Eisman JA (1989) 1,25-dihydroxyvitamin D-responsive element and glucocorticoid repression in the osteocalcin gene. Science 246: 1158–1161Google Scholar
  35. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3 A, and histone deacetylase. Cell 89: 373–380PubMedCrossRefGoogle Scholar
  36. Onate SA, Tsai SY, Tsai MJ, O’Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354–1357PubMedCrossRefGoogle Scholar
  37. Pazin MJ, Kadonaga JT (1997) What’s up and down with histone deacetylation and transcription? Cell 89: 325–328PubMedCrossRefGoogle Scholar
  38. Perissi V, Staszewski LM, McInerney EM, Kurokawa R, Krones A, Rose DW, Lambert MH, Milburn MV, Glass CK, Rosenfeld MG (1999) Molecular determinants of nuclear receptor-corepressor interaction. Genes I)ev 13: 3198–3208CrossRefGoogle Scholar
  39. Poliard A, Bakkali L, Poiret M, Foiret D, Danan JL (1990) Regulation of the rat alpha-fetoprotein gene expression in liver. Both the promoter region and an enhancer element are liver-specific and negatively modulated by dexamethasone. J Biol Chem 265: 2137–2141Google Scholar
  40. Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, Schutz G (1998) DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93: 531–541PubMedCrossRefGoogle Scholar
  41. Saatcioglu F, Claret FX, Karin M (1994) Negative transcriptional regulation by nuclear receptors. Semin Cancer Biol 5: 347–359PubMedGoogle Scholar
  42. Sakai DD, Helms S, Carlstedt-Duke J, Gustafsson JA, Rottman FM, Yamamoto KR (1988) Hormone-mediated repression: a negative glucocorticoid response element from the bovine prolactin gene. Genes Dev 2: 1144–1154PubMedCrossRefGoogle Scholar
  43. Schiile R, Evans RM (1991) Cross-coupling of signal transduction pathways: zinc finger meets leucine zipper. Trends Genet 7: 377–381Google Scholar
  44. Stöcklin E, Wissler M, Gouilleux F, Groner B (1996) Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383: 726–728PubMedCrossRefGoogle Scholar
  45. Strömstedt PE, Poellinger L, Gustafsson JA, Carlstedt-Duke J (1991) The glucocorticoid receptor binds to a sequence overlapping the TATA box of the human osteocalcin promoter: a potential mechanism for negative regulation. Mol Cell Biol 11: 3379–3383PubMedGoogle Scholar
  46. Subramaniam N, Cairns W, Okret S (1997) Studies on the mechanism of glucocorticoid-mediated repression from a negative glucocorticoid response element from the bovine prolactin gene. DNA Cell Biol 16: 153–163PubMedCrossRefGoogle Scholar
  47. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387: 677–684PubMedCrossRefGoogle Scholar
  48. Tsai CC, Kao HY, Yao TP, McKeown M, Evans RM (1999) SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development. Mol Cell 4: 175–186PubMedCrossRefGoogle Scholar
  49. Turcotte B, Meyer ME, Bocquel MT, Belanger L, Chambon P (1990) Repression of the alpha-fetoprotein gene promoter by progesterone and chimeric receptors in the presence of hormones and antihormones. Mol Cell Biol 10: 5002–5006PubMedGoogle Scholar
  50. Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15: 3667–3675PubMedGoogle Scholar
  51. Xu L, Glass CK, Rosenfeld MG (1999) Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev 9: 140–147PubMedCrossRefGoogle Scholar
  52. Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y (1996) A p300/CBP-associated factor that competes with the adenoviral oncoprotein El A. Nature 382: 319–324PubMedCrossRefGoogle Scholar
  53. Yang-Yen HF, Chambard JC, Sun YL, Smeal T, Schmidt TJ, Drouin J, Karin M (1990) Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell 62: 1205–1215PubMedCrossRefGoogle Scholar
  54. Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, Lazar MA (1997) Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc Natl Acad Sci USA 94: 14400–14405PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • A. Dostert
  • T. Heinzel

There are no affiliations available

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