Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Oct;17(10):5952–5959. doi: 10.1128/mcb.17.10.5952

Antagonism between Nur77 and glucocorticoid receptor for control of transcription.

A Philips 1, M Maira 1, A Mullick 1, M Chamberland 1, S Lesage 1, P Hugo 1, J Drouin 1
PMCID: PMC232443  PMID: 9315653

Abstract

Two important functions of glucocorticoids (Gc), namely, suppression of immune system function and feedback repression of the hypothalamo-pituitary-adrenal (HPA) axis, are mediated through repression of gene transcription. Previous studies have indicated that this repression is exerted in part through antagonism between the glucocorticoid receptors (GR) and the AP-1 family of transcription factors. However, this mechanism could not account for repression of the pro-opiomelanocortin (POMC) gene, an important regulator of the HPA axis. Our recent identification of the orphan nuclear receptor Nur77 as a mediator of CRH induction of POMC transcription led us, in the present work, to show that Gc antagonize this positive signal at two levels. First, Gc partly blunt the CRH induction of Nur77 mRNA, and second, they antagonize Nur77-dependent transcription. GR repression is exerted by antagonism of Nur77 action on the NurRE element of the POMC gene. Gc antagonism of NurRE activity was observed in response to physiological stimuli in both endocrine (CRH induction of POMC) and lymphoid (T-cell receptor activation) cells. In transfection experiments, transcriptional activation by Nur77 and the repressor activity of liganded GR titrated each other on their cognate DNA target. In vitro binding experiments as well as mutation analysis of GR suggest that the mechanism of GR antagonism of Nur77 is very similar to that of the antagonism between GR and AP-1. The convergence of positive signals mediated by Nur77 (and also probably by related family members) and negative signals exerted by GR appears to be a general mechanism for control of transcription, since it is active in both endocrine and lymphoid cells.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auphan N., DiDonato J. A., Rosette C., Helmberg A., Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995 Oct 13;270(5234):286–290. doi: 10.1126/science.270.5234.286. [DOI] [PubMed] [Google Scholar]
  2. Boutillier A. L., Monnier D., Lorang D., Lundblad J. R., Roberts J. L., Loeffler J. P. Corticotropin-releasing hormone stimulates proopiomelanocortin transcription by cFos-dependent and -independent pathways: characterization of an AP1 site in exon 1. Mol Endocrinol. 1995 Jun;9(6):745–755. doi: 10.1210/mend.9.6.8592520. [DOI] [PubMed] [Google Scholar]
  3. Caldenhoven E., Liden J., Wissink S., Van de Stolpe A., Raaijmakers J., Koenderman L., Okret S., Gustafsson J. A., Van der Saag P. T. Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. Mol Endocrinol. 1995 Apr;9(4):401–412. doi: 10.1210/mend.9.4.7659084. [DOI] [PubMed] [Google Scholar]
  4. Calnan B. J., Szychowski S., Chan F. K., Cado D., Winoto A. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity. 1995 Sep;3(3):273–282. doi: 10.1016/1074-7613(95)90113-2. [DOI] [PubMed] [Google Scholar]
  5. Cheng L. E., Chan F. K., Cado D., Winoto A. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J. 1997 Apr 15;16(8):1865–1875. doi: 10.1093/emboj/16.8.1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Davis I. J., Lau L. F. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cell Biol. 1994 May;14(5):3469–3483. doi: 10.1128/mcb.14.5.3469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Drouin J., Labrie F. Selective effect of androgens on LH and FSH release in anterior pituitary cells in culture. Endocrinology. 1976 Jun;98(6):1528–1534. doi: 10.1210/endo-98-6-1528. [DOI] [PubMed] [Google Scholar]
  8. Drouin J., Sun Y. L., Chamberland M., Gauthier Y., De Léan A., Nemer M., Schmidt T. J. Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J. 1993 Jan;12(1):145–156. doi: 10.1002/j.1460-2075.1993.tb05640.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Drouin J., Sun Y. L., Tremblay S., Lavender P., Schmidt T. J., de Léan A., Nemer M. Homodimer formation is rate-limiting for high affinity DNA binding by glucocorticoid receptor. Mol Endocrinol. 1992 Aug;6(8):1299–1309. doi: 10.1210/mend.6.8.1406707. [DOI] [PubMed] [Google Scholar]
  10. Drouin J., Trifiro M. A., Plante R. K., Nemer M., Eriksson P., Wrange O. Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. Mol Cell Biol. 1989 Dec;9(12):5305–5314. doi: 10.1128/mcb.9.12.5305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eberwine J. H., Roberts J. L. Glucocorticoid regulation of pro-opiomelanocortin gene transcription in the rat pituitary. J Biol Chem. 1984 Feb 25;259(4):2166–2170. [PubMed] [Google Scholar]
  12. Egan C. R., Chung M. A., Allen F. L., Heschl M. F., Van Buskirk C. L., McGhee J. D. A gut-to-pharynx/tail switch in embryonic expression of the Caenorhabditis elegans ges-1 gene centers on two GATA sequences. Dev Biol. 1995 Aug;170(2):397–419. doi: 10.1006/dbio.1995.1225. [DOI] [PubMed] [Google Scholar]
  13. Gagner J. P., Drouin J. Opposite regulation of pro-opiomelanocortin gene transcription by glucocorticoids and CRH. Mol Cell Endocrinol. 1985 Apr;40(1):25–32. doi: 10.1016/0303-7207(85)90154-6. [DOI] [PubMed] [Google Scholar]
  14. Gagner J. P., Drouin J. Tissue-specific regulation of pituitary proopiomelanocortin gene transcription by corticotropin-releasing hormone, 3',5'-cyclic adenosine monophosphate, and glucocorticoids. Mol Endocrinol. 1987 Oct;1(10):677–682. doi: 10.1210/mend-1-10-677. [DOI] [PubMed] [Google Scholar]
  15. Godowski P. J., Rusconi S., Miesfeld R., Yamamoto K. R. Glucocorticoid receptor mutants that are constitutive activators of transcriptional enhancement. Nature. 1987 Jan 22;325(6102):365–368. doi: 10.1038/325365a0. [DOI] [PubMed] [Google Scholar]
  16. Heck S., Kullmann M., Gast A., Ponta H., Rahmsdorf H. J., Herrlich P., Cato A. C. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO J. 1994 Sep 1;13(17):4087–4095. doi: 10.1002/j.1460-2075.1994.tb06726.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heinzel T., Lavinsky R. M., Mullen T. M., Söderstrom M., Laherty C. D., Torchia J., Yang W. M., Brard G., Ngo S. D., Davie J. R. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997 May 1;387(6628):43–48. doi: 10.1038/387043a0. [DOI] [PubMed] [Google Scholar]
  18. Helmberg A., Auphan N., Caelles C., Karin M. Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 1995 Feb 1;14(3):452–460. doi: 10.1002/j.1460-2075.1995.tb07021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Honkaniemi J., Kononen J., Kainu T., Pyykönen I., Pelto-Huikko M. Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress. Brain Res Mol Brain Res. 1994 Sep;25(3-4):234–241. doi: 10.1016/0169-328x(94)90158-9. [DOI] [PubMed] [Google Scholar]
  20. Hörlein A. J., När A. M., Heinzel T., Torchia J., Gloss B., Kurokawa R., Ryan A., Kamei Y., Söderström M., Glass C. K. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995 Oct 5;377(6548):397–404. doi: 10.1038/377397a0. [DOI] [PubMed] [Google Scholar]
  21. Iwata M., Hanaoka S., Sato K. Rescue of thymocytes and T cell hybridomas from glucocorticoid-induced apoptosis by stimulation via the T cell receptor/CD3 complex: a possible in vitro model for positive selection of the T cell repertoire. Eur J Immunol. 1991 Mar;21(3):643–648. doi: 10.1002/eji.1830210316. [DOI] [PubMed] [Google Scholar]
  22. Jonat C., Rahmsdorf H. J., Park K. K., Cato A. C., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
  23. Kamei Y., Xu L., Heinzel T., Torchia J., Kurokawa R., Gloss B., Lin S. C., Heyman R. A., Rose D. W., Glass C. K. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403–414. doi: 10.1016/s0092-8674(00)81118-6. [DOI] [PubMed] [Google Scholar]
  24. Kerppola T. K., Luk D., Curran T. Fos is a preferential target of glucocorticoid receptor inhibition of AP-1 activity in vitro. Mol Cell Biol. 1993 Jun;13(6):3782–3791. doi: 10.1128/mcb.13.6.3782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. King L. B., Vacchio M. S., Ashwell J. D. To be or not to be: mutually antagonistic death signals regulate thymocyte apoptosis. Int Arch Allergy Immunol. 1994 Dec;105(4):355–358. doi: 10.1159/000236782. [DOI] [PubMed] [Google Scholar]
  26. King L. B., Vacchio M. S., Dixon K., Hunziker R., Margulies D. H., Ashwell J. D. A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity. 1995 Nov;3(5):647–656. doi: 10.1016/1074-7613(95)90135-3. [DOI] [PubMed] [Google Scholar]
  27. König H., Ponta H., Rahmsdorf H. J., Herrlich P. Interference between pathway-specific transcription factors: glucocorticoids antagonize phorbol ester-induced AP-1 activity without altering AP-1 site occupation in vivo. EMBO J. 1992 Jun;11(6):2241–2246. doi: 10.1002/j.1460-2075.1992.tb05283.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lamonerie T., Tremblay J. J., Lanctôt C., Therrien M., Gauthier Y., Drouin J. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev. 1996 May 15;10(10):1284–1295. doi: 10.1101/gad.10.10.1284. [DOI] [PubMed] [Google Scholar]
  29. Liu Z. G., Smith S. W., McLaughlin K. A., Schwartz L. M., Osborne B. A. Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature. 1994 Jan 20;367(6460):281–284. doi: 10.1038/367281a0. [DOI] [PubMed] [Google Scholar]
  30. Murphy E. P., Conneely O. M. Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors. Mol Endocrinol. 1997 Jan;11(1):39–47. doi: 10.1210/mend.11.1.9874. [DOI] [PubMed] [Google Scholar]
  31. Nagy L., Kao H. Y., Chakravarti D., Lin R. J., Hassig C. A., Ayer D. E., Schreiber S. L., Evans R. M. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997 May 2;89(3):373–380. doi: 10.1016/s0092-8674(00)80218-4. [DOI] [PubMed] [Google Scholar]
  32. Oñate S. A., Tsai S. Y., Tsai M. J., O'Malley B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354–1357. doi: 10.1126/science.270.5240.1354. [DOI] [PubMed] [Google Scholar]
  33. Parkes D., Rivest S., Lee S., Rivier C., Vale W. Corticotropin-releasing factor activates c-fos, NGFI-B, and corticotropin-releasing factor gene expression within the paraventricular nucleus of the rat hypothalamus. Mol Endocrinol. 1993 Oct;7(10):1357–1367. doi: 10.1210/mend.7.10.8264665. [DOI] [PubMed] [Google Scholar]
  34. Philips A., Lesage S., Gingras R., Maira M. H., Gauthier Y., Hugo P., Drouin J. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol. 1997 Oct;17(10):5946–5951. doi: 10.1128/mcb.17.10.5946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Riegel A. T., Lu Y., Remenick J., Wolford R. G., Berard D. S., Hager G. L. Proopiomelanocortin gene promoter elements required for constitutive and glucocorticoid-repressed transcription. Mol Endocrinol. 1991 Dec;5(12):1973–1982. doi: 10.1210/mend-5-12-1973. [DOI] [PubMed] [Google Scholar]
  36. Scheinman R. I., Cogswell P. C., Lofquist A. K., Baldwin A. S., Jr Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995 Oct 13;270(5234):283–286. doi: 10.1126/science.270.5234.283. [DOI] [PubMed] [Google Scholar]
  37. Scheinman R. I., Gualberto A., Jewell C. M., Cidlowski J. A., Baldwin A. S., Jr Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol. 1995 Feb;15(2):943–953. doi: 10.1128/mcb.15.2.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schüle R., Rangarajan P., Kliewer S., Ransone L. J., Bolado J., Yang N., Verma I. M., Evans R. M. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell. 1990 Sep 21;62(6):1217–1226. doi: 10.1016/0092-8674(90)90397-w. [DOI] [PubMed] [Google Scholar]
  39. Sgonc R., Boeck G., Dietrich H., Gruber J., Recheis H., Wick G. Simultaneous determination of cell surface antigens and apoptosis. Trends Genet. 1994 Feb;10(2):41–42. doi: 10.1016/0168-9525(94)90140-6. [DOI] [PubMed] [Google Scholar]
  40. Therrien M., Drouin J. Cell-specific helix-loop-helix factor required for pituitary expression of the pro-opiomelanocortin gene. Mol Cell Biol. 1993 Apr;13(4):2342–2353. doi: 10.1128/mcb.13.4.2342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Therrien M., Drouin J. Pituitary pro-opiomelanocortin gene expression requires synergistic interactions of several regulatory elements. Mol Cell Biol. 1991 Jul;11(7):3492–3503. doi: 10.1128/mcb.11.7.3492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wilson T. E., Fahrner T. J., Johnston M., Milbrandt J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science. 1991 May 31;252(5010):1296–1300. doi: 10.1126/science.1925541. [DOI] [PubMed] [Google Scholar]
  43. Wolffe A. P. Transcriptional control. Sinful repression. Nature. 1997 May 1;387(6628):16–17. doi: 10.1038/387016a0. [DOI] [PubMed] [Google Scholar]
  44. Woronicz J. D., Calnan B., Ngo V., Winoto A. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature. 1994 Jan 20;367(6460):277–281. doi: 10.1038/367277a0. [DOI] [PubMed] [Google Scholar]
  45. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES