Disease relevance of NR3C1

• OBJECTIVE: To test the associations between the N363S polymorphism of the glucocorticoid receptor gene (NR3C1) and factors related to the metabolic syndrome in middle-aged men with and without juvenile-onset obesity [1].
• Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia [2].
• RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158) [3].
• In conclusion, GR/NF-kappaB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long-standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia [4].
• Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival [5].

Psychiatry related information on NR3C1

• Compared with control subjects, GR mRNA expression was reduced in the basolateral/lateral nuclei in schizophrenia and bipolar disorder [6].
• Both mental health of humans and animal welfare is likely to be seriously threatened after psychosocial stress, prolonged stress, prenatal stress or postnatal stress, especially when maternal care or social support is absent, because these can chronically dysregulate the central MR/GR balance [7].
• Glucocorticoid receptor gene expression is unaltered in hippocampal neurons in Alzheimer's disease [8].
• Since glucocorticoid hypersecretion occurs in Alzheimer's-type dementia it has been proposed that a primary reduction in hippocampal glucocorticoid receptor expression leads to failure of feedback, hypercortisolemia and hence further neuronal loss [8].
• Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists [9].

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

• Steroid hormone receptor gene expression in human breast cancer cells: inverse relationship between oestrogen and glucocorticoid receptor messenger RNA levels [14].
• This effect of melatonin on ERalpha and GR is blocked by pertussis toxin (PTX) suggesting that melatonin's actions may be mediated via a PTX-sensitive G(alphai) protein [15].
• In leukemia and lymphoma, mutations in the glucocorticoid receptor (GR) cause resistance to cell lysis by dexamethasone [16].
• HPLC micromethod for simultaneous measurement of estradiol, progesterone, androgen and glucocorticoid receptor levels. Application to breast cancer biopsies [17].
• The HIV-1 protein Vpr has glucocorticoid receptor coactivator activity, potently increasing the sensitivity of glucocorticoid target tissues to cortisol [18].

Biological context of NR3C1

• NR3C1 is located on chromosome 5q31 and contains 10 exons that code for a 777 amino acid protein [19].
• Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population [20].
• Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response element [21].
• Together, these proteins make up the inactive GR, thus biochemically linking two families of proteins proposed to be involved in protein folding and assembly as well as two potent immunosuppressive modalities [22].
• An open reading frame from yeast, which is highly homologous, encodes the previously uncharacterized 73-kD subunit of the yeast SWI/SNF complex required for transcriptional activation by the glucocorticoid receptor (Cairns et al., this issue) [23].

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

• Here we demonstrate that activated JNK phosphorylates human GR at Ser226 and enhances its nuclear export after withdrawal of a ligand for GR, dexamethasone [35].
• Furthermore, squirrel monkey FKBP51 in which either FK1 or FK2 was deleted lacked GR inhibitory activity [36].

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

• TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain [31].
• Using mammalian two-hybrid assays, we demonstrate that GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains [32].
• These data suggest that the local recruitment of GR causes repression by inhibiting transcriptional activation by GATA3, a key tissue-specific determinant of expression of Th2 cytokines [38].
• Immunoprecipitation and sucrose gradient centrifugation studies demonstrated the association of hsp70 with both the nonactivated and in vitro activated hGR [39].
• Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation [35].

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

• We found that CRT mediates nuclear export of GR in permeabilized cell, microinjection, and transfection assays [42].
• Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, GR coprecipitates with MTI-II, and, vice versa, MTI-II coprecipitates with GR [43].
• Western blot analysis performed on endometrial tumor cell lines of glandular (HEC-1B) and mesodermal (SKUT-1B) origin, respectively, showed GR expression only in the latter [44].
• In the present study, we used immunohistochemistry to analyze the expression of GR in the normal human endometrium throughout the menstrual cycle [44].
• In addition, quantitative PCR shows that DEX down-regulates GR and up-regulates glucocorticoid-induced leucine zipper levels, whereas ICI 182,780 does not counteract these effects [45].

References