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Gene Review

Nr3c1  -  nuclear receptor subfamily 3, group C,...

Mus musculus

Synonyms: GR, Glucocorticoid receptor, Grl, Grl-1, Grl1, ...
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Disease relevance of Nr3c1

  • We previously found that during fibrosarcoma (FS) progression, GR displays only modest transcriptional activity in the preneoplastic stages, whereas it is highly active in FS cells [1].
  • This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery [2].
  • Importantly, exogenous p16(INK4a) introduced by cotransfection is sufficient to reduce GR activity in FS cells, without affecting GR activity in p16-positive aggressive fibromatosis cells [1].
  • The mouse mammary tumor virus promoter adopts distinct chromatin structures in human breast cancer cells with and without glucocorticoid receptor [3].
  • Glucocorticoids, acting through the glucocorticoid receptor, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions, autoimmune diseases, leukemias and lymphomas [4].

Psychiatry related information on Nr3c1


High impact information on Nr3c1


Chemical compound and disease context of Nr3c1


Biological context of Nr3c1

  • We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model [2].
  • Treatment with the demethylating agent 5-aza-2'-deoxycytidine restores p16(INK4a) expression and reverts the phenotype of FS cells to low GR transcriptional activity, similar to that of the p16(INK4a)-expressing preneoplastic stages [1].
  • These results suggest a relationship between steroid hormone receptor activity and cell cycle inhibition, whereby absence of p16(INK4a) protein leads to higher GR transactivation activity and reduced cell sensitivity to dexamethasone [1].
  • Although the GR does not bind the Stat5 DNA binding site directly, it could be detected with the Stat5-DNA complex [20].
  • In contrast, the loss of GR did not result in overt phenotypic changes in mammary gland development during pregnancy, lactation, and involution [21].

Anatomical context of Nr3c1

  • Furthermore, GR transcriptional activity is elevated in mouse embryo fibroblasts derived from INK4a(-/-) mice compared with those derived from WT mice, implying that the difference in p16(INK4a) expression is sufficient to modulate GR activity [1].
  • Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability [5].
  • Increased glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice [22].
  • Mineralocorticoid versus glucocorticoid receptor occupancy mediating aldosterone-stimulated sodium transport in a novel renal cell line [23].
  • Neuropathological analyses revealed a decreased density of granule cells in the hippocampus of adult MR-/- mice but not in mice with disruption of GR [24].

Associations of Nr3c1 with chemical compounds


Physical interactions of Nr3c1


Enzymatic interactions of Nr3c1

  • This is in good agreement with the demonstration that the DNA binding-defective GR is still able to interact with phosphorylated Stat5 proteins, suggesting that transcriptional regulation by protein-protein interaction forms the basis of glucocorticoid action in this process [32].

Regulatory relationships of Nr3c1


Other interactions of Nr3c1

  • Loss of p16INK4a results in increased glucocorticoid receptor activity during fibrosarcoma development [1].
  • These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development [21].
  • Replacement of residues encompassing helices 1-5 of GR with those of PR yields a receptor that is nuclear [36].
  • Taken together, these results demonstrate that activation of p38 MAPK pathways are involved in IL-1alpha-mediated inhibition of GR function [25].
  • Neither the minerolocorticoid receptor (MR) nor the pregnane X receptor (PXR) showed compensatory up-regulation in GR-/- mice [37].

Analytical, diagnostic and therapeutic context of Nr3c1


  1. Loss of p16INK4a results in increased glucocorticoid receptor activity during fibrosarcoma development. Roca, R., Kypta, R.M., Vivanco, M.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Anthrax lethal factor represses glucocorticoid and progesterone receptor activity. Webster, J.I., Tonelli, L.H., Moayeri, M., Simons, S.S., Leppla, S.H., Sternberg, E.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. The mouse mammary tumor virus promoter adopts distinct chromatin structures in human breast cancer cells with and without glucocorticoid receptor. Kinyamu, H.K., Fryer, C.J., Horwitz, K.B., Archer, T.K. J. Biol. Chem. (2000) [Pubmed]
  4. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Brewer, J.A., Khor, B., Vogt, S.K., Muglia, L.M., Fujiwara, H., Haegele, K.E., Sleckman, B.P., Muglia, L.J. Nat. Med. (2003) [Pubmed]
  5. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability. Wei, Q., Lu, X.Y., Liu, L., Schafer, G., Shieh, K.R., Burke, S., Robinson, T.E., Watson, S.J., Seasholtz, A.F., Akil, H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. Speirs, H.J., Seckl, J.R., Brown, R.W. J. Endocrinol. (2004) [Pubmed]
  7. Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress. Froger, N., Palazzo, E., Boni, C., Hanoun, N., Saurini, F., Joubert, C., Dutriez-Casteloot, I., Enache, M., Maccari, S., Barden, N., Cohen-Salmon, C., Hamon, M., Lanfumey, L. J. Neurosci. (2004) [Pubmed]
  8. Glucocorticoid receptor blockade disinhibits pituitary-adrenal activity during the stress hyporesponsive period of the mouse. Schmidt, M.V., Schmidt, M., Levine, S., Oitzl, M.S., van der Mark, M., Müller, M.B., Holsboer, F., de Kloet, E.R. Endocrinology (2005) [Pubmed]
  9. Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice. Evrard, A., Barden, N., Hamon, M., Adrien, J. Sleep. (2006) [Pubmed]
  10. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R.K., Westin, S., Hoffmann, A., Subramaniam, S., David, M., Rosenfeld, M.G., Glass, C.K. Cell (2005) [Pubmed]
  11. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Kliewer, S.A., Moore, J.T., Wade, L., Staudinger, J.L., Watson, M.A., Jones, S.A., McKee, D.D., Oliver, B.B., Willson, T.M., Zetterström, R.H., Perlmann, T., Lehmann, J.M. Cell (1998) [Pubmed]
  12. DNA binding of the glucocorticoid receptor is not essential for survival. Reichardt, H.M., Kaestner, K.H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P., Schütz, G. Cell (1998) [Pubmed]
  13. Reversible and persistent changes in chromatin structure accompany activation of a glucocorticoid-dependent enhancer element. Zaret, K.S., Yamamoto, K.R. Cell (1984) [Pubmed]
  14. Chromosome assignment of a murine glucocorticoid receptor gene (Grl-1) using intraspecies somatic cell hybrids. Francke, U., Gehring, U. Cell (1980) [Pubmed]
  15. Transcriptional control of steroid-regulated apoptosis in murine thymoma cells. Chapman, M.S., Askew, D.J., Kuscuoglu, U., Miesfeld, R.L. Mol. Endocrinol. (1996) [Pubmed]
  16. Mineralocorticoid receptor mediates glucocorticoid treatment effects in the autoimmune mouse ear. Trune, D.R., Kempton, J.B., Gross, N.D. Hear. Res. (2006) [Pubmed]
  17. Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. Nishimura, K., Nonomura, N., Satoh, E., Harada, Y., Nakayama, M., Tokizane, T., Fukui, T., Ono, Y., Inoue, H., Shin, M., Tsujimoto, Y., Takayama, H., Aozasa, K., Okuyama, A. J. Natl. Cancer Inst. (2001) [Pubmed]
  18. The receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in the mouse hepatoma cell line Hepa 1c1c7. A comparison with the glucocorticoid receptor and the mouse and rat hepatic dioxin receptors. Cuthill, S., Poellinger, L., Gustafsson, J.A. J. Biol. Chem. (1987) [Pubmed]
  19. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Opherk, C., Tronche, F., Kellendonk, C., Kohlmüller, D., Schulze, A., Schmid, W., Schütz, G. Mol. Endocrinol. (2004) [Pubmed]
  20. Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. Cella, N., Groner, B., Hynes, N.E. Mol. Cell. Biol. (1998) [Pubmed]
  21. The mineralocorticoid receptor may compensate for the loss of the glucocorticoid receptor at specific stages of mammary gland development. Kingsley-Kallesen, M., Mukhopadhyay, S.S., Wyszomierski, S.L., Schanler, S., Schütz, G., Rosen, J.M. Mol. Endocrinol. (2002) [Pubmed]
  22. Increased glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice. Liu, Y., Nakagawa, Y., Wang, Y., Sakurai, R., Tripathi, P.V., Lutfy, K., Friedman, T.C. Diabetes (2005) [Pubmed]
  23. Mineralocorticoid versus glucocorticoid receptor occupancy mediating aldosterone-stimulated sodium transport in a novel renal cell line. Gaeggeler, H.P., Gonzalez-Rodriguez, E., Jaeger, N.F., Loffing-Cueni, D., Norregaard, R., Loffing, J., Horisberger, J.D., Rossier, B.C. J. Am. Soc. Nephrol. (2005) [Pubmed]
  24. Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice. Gass, P., Kretz, O., Wolfer, D.P., Berger, S., Tronche, F., Reichardt, H.M., Kellendonk, C., Lipp, H.P., Schmid, W., Schütz, G. EMBO Rep. (2000) [Pubmed]
  25. Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Wang, X., Wu, H., Miller, A.H. Mol. Psychiatry (2004) [Pubmed]
  26. Progesterone Receptor Repression of Prolactin/Signal Transducer and Activator of Transcription 5-Mediated Transcription of the {beta}-Casein Gene in Mammary Epithelial Cells. Buser, A.C., Gass-Handel, E.K., Wyszomierski, S.L., Doppler, W., Leonhardt, S.A., Schaack, J., Rosen, J.M., Watkin, H., Anderson, S.M., Edwards, D.P. Mol. Endocrinol. (2007) [Pubmed]
  27. Developmental and hormonal regulation of progesterone receptor A-form expression in female mouse lung in vivo: interaction with glucocorticoid receptors. Shao, R., Egecioglu, E., Weijdeg??rd, B., Ljungstr??m, K., Ling, C., Fernandez-Rodriguez, J., Billig, H. J. Endocrinol. (2006) [Pubmed]
  28. Binding of androgen-receptor complexes to alpha 2u-globulin genes and to the long terminal repeat of mouse mammary tumor virus. Van Dijck, P., Winderickx, J., Heyns, W., Verhoeven, G. Mol. Cell. Endocrinol. (1989) [Pubmed]
  29. Chronic glucocorticoid receptor activation impairs CREB transcriptional activity in clonal neurons. Föcking, M., Hölker, I., Trapp, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  30. Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor. Meijer, O.C., Cole, T.J., Schmid, W., Schütz, G., Joëls, M., De Kloet, E.R. Brain Res. Mol. Brain Res. (1997) [Pubmed]
  31. Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway. Schmidt, P., Holsboer, F., Spengler, D. Mol. Endocrinol. (2001) [Pubmed]
  32. Mammary gland development and lactation are controlled by different glucocorticoid receptor activities. Reichardt, H.M., Horsch, K., Gröne, H.J., Kolbus, A., Beug, H., Hynes, N., Schütz, G. Eur. J. Endocrinol. (2001) [Pubmed]
  33. Interactive regulation of Ah and glucocorticoid receptors in the synergistic induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin and hydrocortisone. Abbott, B.D., Perdew, G.H., Buckalew, A.R., Birnbaum, L.S. Toxicol. Appl. Pharmacol. (1994) [Pubmed]
  34. The establishment of the long terminal repeat of the mouse mammary tumor virus into CV-1 cells allows a functional analysis of steroid receptors. Couette, B., Le Ricousse, S., Fortin, D., Rafestin-Oblin, M.E., Richard-Foy, H. Biochim. Biophys. Acta (1994) [Pubmed]
  35. Glucocorticoids, TGF-beta, and embryonic mouse salivary gland morphogenesis. Jaskoll, T., Choy, H.A., Melnick, M. J. Craniofac. Genet. Dev. Biol. (1994) [Pubmed]
  36. Separable features of the ligand-binding domain determine the differential subcellular localization and ligand-binding specificity of glucocorticoid receptor and progesterone receptor. Wan, Y., Coxe, K.K., Thackray, V.G., Housley, P.R., Nordeen, S.K. Mol. Endocrinol. (2001) [Pubmed]
  37. Development of the fetal intestine in mice lacking the glucocorticoid receptor (GR). Gartner, H., Graul, M.C., Oesterreicher, T.J., Finegold, M.J., Henning, S.J. J. Cell. Physiol. (2003) [Pubmed]
  38. Evaluation of steroid receptor function by gene targeting in mice. Wintermantel, T.M., Berger, S., Greiner, E.F., Schütz, G. J. Steroid Biochem. Mol. Biol. (2005) [Pubmed]
  39. RT-PCR quantification of AHR, ARNT, GR, and CYP1A1 mRNA in craniofacial tissues of embryonic mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and hydrocortisone. Abbott, B.D., Schmid, J.E., Brown, J.G., Wood, C.R., White, R.D., Buckalew, A.R., Held, G.A. Toxicol. Sci. (1999) [Pubmed]
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