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Gene Review

NR3C1  -  nuclear receptor subfamily 3, group C,...

Homo sapiens

Synonyms: GCCR, GCR, GCRST, GR, GRL, ...
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Disease relevance of NR3C1


Psychiatry related information on NR3C1


High impact information on NR3C1

  • Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules [10].
  • It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function [11].
  • We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples [12].
  • Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2 [13].
  • Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular beta sheet [13].

Chemical compound and disease context of NR3C1


Biological context of NR3C1


Anatomical context of NR3C1

  • In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-kappa B at the levels of both DNA binding and transcriptional activation [24].
  • Transient transfection of different cell lines with a steroid-responsive reporter plasmid and receptor expression plasmids revealed that transcriptional activity mediated by GR in response to agonists was strongly suppressed by coexpression of ERR2 [25].
  • Thus, we propose that PP5 possesses properties of an immunophilin with low affinity FK506 binding activity and that it determines a major portion of the native GR heterocomplexes in L cell cytosol [26].
  • In an effort to dissect the mechanisms of GR-mediated breast epithelial cell survival, we now examine the molecular events downstream of GR activation [5].
  • Our results show that Cdc37 binds to AR but not to glucocorticoid receptors (GR) synthesized in rabbit reticulocyte lysates [27].

Associations of NR3C1 with chemical compounds

  • The activities of GR and MR at plfG, a 25-base pair composite response element to which both the steroid receptors and transcription factor AP1 can bind, are analyzed here [21].
  • With the use of MR-GR chimeras, a segment of the NH2-terminal region of GR (amino acids 105 to 440) was shown to be required for this repression [21].
  • We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment [28].
  • The hormone-activated glucocorticoid receptor (GR), through its N- and C-terminal transcriptional activation functions AF-1 and AF-2, controls the transcription of target genes presumably through interaction(s) with transcriptional regulatory factors [29].
  • A repeated sequence motif [EEX(4)](8) at the NH(2) terminus of RAP46 or BAG-1L, a larger isoform of RAP46, is responsible for this downregulation of GR activity [30].

Physical interactions of NR3C1

  • Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm [2].
  • Our results show that recombinant GR AF1 acquires a significant amount of helical content when it interacts with TBP [31].
  • Finally, we show that GR interacts with Smad3 both in vitro and in vivo [32].
  • We show that in the absence of its ligand-binding domain, the glucocorticoid receptor (GR) is able to interact with both nuclear receptor coactivators and the BRG1 chromatin-remodeling complex in vivo [33].
  • Physical interaction required activation of Smad3 by TGF-beta but not dexamethasone binding to GR [34].

Enzymatic interactions of NR3C1


Co-localisations of NR3C1

  • Endogenous STAMP colocalizes with GR in intact cells and is recruited to the promoters of endogenous GR-induced and -repressed genes [37].

Regulatory relationships of NR3C1


Other interactions of NR3C1

  • These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival [2].
  • When IL-6 and Dex are removed (after 30 min of treatment), the disappearance within an additional 30 min of the established enhanceosome indicates that renewal of STAT3 and GR binding must occur in the continued presence of IL-6+Dex [40].
  • Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2 [2].
  • Mutations swapping a single residue at position 848 from helix H7 between MR and glucocorticoid receptor (GR) switch their hormone specificity [41].
  • Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma [28].

Analytical, diagnostic and therapeutic context of NR3C1


  1. The N363S polymorphism of the glucocorticoid receptor and metabolic syndrome factors in men. Buemann, B., Black, E., Holst, C., Toubro, S., Echwald, S., Pedersen, O., Astrup, A., Sørensen, T. Obes. Res. (2005) [Pubmed]
  2. Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. Sengupta, S., Wasylyk, B. Genes Dev. (2001) [Pubmed]
  3. Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. Chang, J., Powles, T.J., Allred, D.C., Ashley, S.E., Clark, G.M., Makris, A., Assersohn, L., Gregory, R.K., Osborne, C.K., Dowsett, M. J. Clin. Oncol. (1999) [Pubmed]
  4. Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Assenat, E., Gerbal-Chaloin, S., Larrey, D., Saric, J., Fabre, J.M., Maurel, P., Vilarem, M.J., Pascussi, J.M. Hepatology (2004) [Pubmed]
  5. Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. Wu, W., Pew, T., Zou, M., Pang, D., Conzen, S.D. J. Biol. Chem. (2005) [Pubmed]
  6. Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness. Perlman, W.R., Webster, M.J., Kleinman, J.E., Weickert, C.S. Biol. Psychiatry (2004) [Pubmed]
  7. Corticosteroids in relation to fear, anxiety and psychopathology. Korte, S.M. Neuroscience and biobehavioral reviews. (2001) [Pubmed]
  8. Glucocorticoid receptor gene expression is unaltered in hippocampal neurons in Alzheimer's disease. Seckl, J.R., French, K.L., O'Donnell, D., Meaney, M.J., Nair, N.P., Yates, C.M., Fink, G. Brain Res. Mol. Brain Res. (1993) [Pubmed]
  9. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Zarate, C.A., Singh, J., Manji, H.K. Biol. Psychiatry (2006) [Pubmed]
  10. Neuroendocrine regulation of immunity. Webster, J.I., Tonelli, L., Sternberg, E.M. Annu. Rev. Immunol. (2002) [Pubmed]
  11. Glucocorticoids in T cell development and function*. Ashwell, J.D., Lu, F.W., Vacchio, M.S. Annu. Rev. Immunol. (2000) [Pubmed]
  12. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Binder, E.B., Salyakina, D., Lichtner, P., Wochnik, G.M., Ising, M., Pütz, B., Papiol, S., Seaman, S., Lucae, S., Kohli, M.A., Nickel, T., Künzel, H.E., Fuchs, B., Majer, M., Pfennig, A., Kern, N., Brunner, J., Modell, S., Baghai, T., Deiml, T., Zill, P., Bondy, B., Rupprecht, R., Messer, T., Köhnlein, O., Dabitz, H., Brückl, T., Müller, N., Pfister, H., Lieb, R., Mueller, J.C., Lõhmussaar, E., Strom, T.M., Bettecken, T., Meitinger, T., Uhr, M., Rein, T., Holsboer, F., Muller-Myhsok, B. Nat. Genet. (2004) [Pubmed]
  13. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Bledsoe, R.K., Montana, V.G., Stanley, T.B., Delves, C.J., Apolito, C.J., McKee, D.D., Consler, T.G., Parks, D.J., Stewart, E.L., Willson, T.M., Lambert, M.H., Moore, J.T., Pearce, K.H., Xu, H.E. Cell (2002) [Pubmed]
  14. Steroid hormone receptor gene expression in human breast cancer cells: inverse relationship between oestrogen and glucocorticoid receptor messenger RNA levels. Hall, R.E., Lee, C.S., Alexander, I.E., Shine, J., Clarke, C.L., Sutherland, R.L. Int. J. Cancer (1990) [Pubmed]
  15. Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. Kiefer, T.L., Lai, L., Yuan, L., Dong, C., Burow, M.E., Hill, S.M. J. Pineal Res. (2005) [Pubmed]
  16. Hormone resistance in cancer: the role of abnormal steroid receptors. Sluyser, M. Critical reviews in oncogenesis. (1994) [Pubmed]
  17. HPLC micromethod for simultaneous measurement of estradiol, progesterone, androgen and glucocorticoid receptor levels. Application to breast cancer biopsies. Formento, J.L., Moll, J.L., Francoual, M., Krebs, B.P., Milano, G., Renee, N., Khater, R., Frenay, M., Namer, M. European journal of cancer & clinical oncology. (1987) [Pubmed]
  18. HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection. Mirani, M., Elenkov, I., Volpi, S., Hiroi, N., Chrousos, G.P., Kino, T. J. Immunol. (2002) [Pubmed]
  19. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Bray, P.J., Cotton, R.G. Hum. Mutat. (2003) [Pubmed]
  20. Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population. Koyano, S., Saito, Y., Sai, K., Kurose, K., Ozawa, S., Nakajima, T., Matsumoto, K., Saito, H., Shirao, K., Yoshida, T., Minami, H., Ohtsu, A., Saijo, N., Sawada, J. Drug Metab. Pharmacokinet. (2005) [Pubmed]
  21. Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response element. Pearce, D., Yamamoto, K.R. Science (1993) [Pubmed]
  22. Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex. Tai, P.K., Albers, M.W., Chang, H., Faber, L.E., Schreiber, S.L. Science (1992) [Pubmed]
  23. Diversity and specialization of mammalian SWI/SNF complexes. Wang, W., Xue, Y., Zhou, S., Kuo, A., Cairns, B.R., Crabtree, G.R. Genes Dev. (1996) [Pubmed]
  24. Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Scheinman, R.I., Gualberto, A., Jewell, C.M., Cidlowski, J.A., Baldwin, A.S. Mol. Cell. Biol. (1995) [Pubmed]
  25. Nuclear orphan receptor as a repressor of glucocorticoid receptor transcriptional activity. Trapp, T., Holsboer, F. J. Biol. Chem. (1996) [Pubmed]
  26. Protein phosphatase 5 is a major component of glucocorticoid receptor.hsp90 complexes with properties of an FK506-binding immunophilin. Silverstein, A.M., Galigniana, M.D., Chen, M.S., Owens-Grillo, J.K., Chinkers, M., Pratt, W.B. J. Biol. Chem. (1997) [Pubmed]
  27. Functional interaction of human Cdc37 with the androgen receptor but not with the glucocorticoid receptor. Rao, J., Lee, P., Benzeno, S., Cardozo, C., Albertus, J., Robins, D.M., Caplan, A.J. J. Biol. Chem. (2001) [Pubmed]
  28. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. Adcock, I.M., Lane, S.J., Brown, C.R., Lee, T.H., Barnes, P.J. J. Exp. Med. (1995) [Pubmed]
  29. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. Hittelman, A.B., Burakov, D., Iñiguez-Lluhí, J.A., Freedman, L.P., Garabedian, M.J. EMBO J. (1999) [Pubmed]
  30. A nuclear action of the eukaryotic cochaperone RAP46 in downregulation of glucocorticoid receptor activity. Schneikert, J., Hübner, S., Martin, E., Cato, A.C. J. Cell Biol. (1999) [Pubmed]
  31. TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain. Kumar, R., Volk, D.E., Li, J., Lee, J.C., Gorenstein, D.G., Thompson, E.B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  32. Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Song, C.Z., Tian, X., Gelehrter, T.D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  33. BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation. Hsiao, P.W., Fryer, C.J., Trotter, K.W., Wang, W., Archer, T.K. Mol. Cell. Biol. (2003) [Pubmed]
  34. Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. Li, G., Wang, S., Gelehrter, T.D. J. Biol. Chem. (2003) [Pubmed]
  35. Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation. Itoh, M., Adachi, M., Yasui, H., Takekawa, M., Tanaka, H., Imai, K. Mol. Endocrinol. (2002) [Pubmed]
  36. Structure-function analysis of squirrel monkey FK506-binding protein 51, a potent inhibitor of glucocorticoid receptor activity. Denny, W.B., Prapapanich, V., Smith, D.F., Scammell, J.G. Endocrinology (2005) [Pubmed]
  37. STAMP, a Novel Predicted Factor Assisting TIF2 Actions in Glucocorticoid Receptor-Mediated Induction and Repression. He, Y., Simons, S.S. Mol. Cell. Biol. (2007) [Pubmed]
  38. Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment. Jee, Y.K., Gilmour, J., Kelly, A., Bowen, H., Richards, D., Soh, C., Smith, P., Hawrylowicz, C., Cousins, D., Lee, T., Lavender, P. J. Biol. Chem. (2005) [Pubmed]
  39. Heat shock protein is tightly associated with the recombinant human glucocorticoid receptor:glucocorticoid response element complex. Srinivasan, G., Patel, N.T., Thompson, E.B. Mol. Endocrinol. (1994) [Pubmed]
  40. STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene. Lerner, L., Henriksen, M.A., Zhang, X., Darnell, J.E. Genes Dev. (2003) [Pubmed]
  41. Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Li, Y., Suino, K., Daugherty, J., Xu, H.E. Mol. Cell (2005) [Pubmed]
  42. Calreticulin Is a receptor for nuclear export. Holaska, J.M., Black, B.E., Love, D.C., Hanover, J.A., Leszyk, J., Paschal, B.M. J. Cell Biol. (2001) [Pubmed]
  43. Macromolecular translocation inhibitor II (Zn(2+)-binding protein, parathymosin) interacts with the glucocorticoid receptor and enhances transcription in vivo. Okamoto, K., Isohashi, F. J. Biol. Chem. (2005) [Pubmed]
  44. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. Bamberger, A.M., Milde-Langosch, K., Löning, T., Bamberger, C.M. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  45. Estrogen Receptor Antagonist Fulvestrant (ICI 182,780) Inhibits the Anti-Inflammatory Effect of Glucocorticoids. Cuzzocrea, S., Bruscoli, S., Crisafulli, C., Mazzon, E., Agostini, M., Mui??, C., Esposito, E., Di Virgilio, R., Meli, R., Vegeto, E., Maggi, A., Riccardi, C. Mol. Pharmacol. (2007) [Pubmed]
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