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

• This finding suggests that natural variations in GR gene expression can contribute to the fine-tuning of emotional stability or lability and may play a role in bipolar disorder [5].
• Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development [6].
• These results demonstrate that impaired GR functioning affects normal adaptive responses of the HPA axis and 5-HT system to CMS and alters stress-related consequences on decision-making behaviors [7].
• For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation [8].
• Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice [9].

High impact information on Nr3c1

• This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression [10].
• Notably, PXR.1 is efficaciously activated by pregnenolone 16alpha-carbonitrile, a glucocorticoid receptor antagonist that induces the expression of the CYP3A family of steroid hydroxylases and modulates sterol and bile acid biosynthesis in vivo [11].
• In order to separate these modes of action, we introduced the point mutation A458T into the GR by gene targeting using the Cre/loxP system [12].
• The induced hypersensitive region coincides with a segment of the MTV long terminal repeat sequence that specifically binds purified glucocorticoid receptor in vitro and functions as a hormone-dependent enhancer element in vivo [13].
• Chromosome assignment of a murine glucocorticoid receptor gene (Grl-1) using intraspecies somatic cell hybrids [14].

Chemical compound and disease context of Nr3c1

• GR expression levels were shown to be rate-limiting for initiating the apoptotic pathway, and a positive correlation between steroid sensitivity and GR-mediated induction of an integrated mouse mammary tumor virus (MMTV) LTR reporter gene was observed [15].
• The spironolactone treatment did not block normal glucocorticoid receptor-mediated immune-suppression functions because mice receiving prednisolone, either with or without spironolactone, maintained normal body weights, hematocrits, and serum immune complexes [16].
• METHODS: Three human prostate cancer cell lines (DU145, PC-3, and LNCaP) were assessed for GR expression and responsiveness to dexamethasone [17].
• 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 [18].
• These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia [19].

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

• 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver [22].
• Previous studies have demonstrated that interleukinalpha (IL-1alpha) inhibits glucocorticoid receptor (GR) nuclear translocation and dexamethasone (Dex)-induced gene transcription [25].
• Furthermore, adult MR-/- mice exhibited a significant reduction of granule cell neurogenesis to 65% of control levels, possibly mediated by GR due to elevated corticosterone plasma levels [24].
• Mineralocorticoid specificity is ensured by 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR [23].
• These results define a negative cross talk between PR and Stat5a/GR that may contribute to the physiological role of progesterone to repress lactogenic hormone induction of the beta-casein gene in the mammary gland during pregnancy [26].

Physical interactions of Nr3c1

• Furthermore, immunoprecipitation followed by Western blot analysis revealed that, under in vivo conditions, PRA physically interacted with GR in mouse lung [27].
• The region of RAP 01 which binds androgen-receptor complexes has previously been shown to interact with glucocorticoid receptors and contains a 17 bp sequence homologous with the consensus sequence for glucocorticoid-receptor binding [28].
• We provide evidence that chronic activation of the glucocorticoid receptor (GR) in clonal neurons inhibits the transcriptional activity of the cyclic AMP response element-binding protein (CREB), which is believed to be involved in memory processes [29].
• Regulation of hippocampal 5-HT1A receptor mRNA and binding in transgenic mice with a targeted disruption of the glucocorticoid receptor [30].
• This enhancement was strongest at low concentrations of glucocorticoids and was accompanied by increased GR binding to a glucocorticoid-responsive element (GRE). beta(2)-Adrenergic receptor-mediated GR enhancement was relayed via G protein beta gamma-subunits, insensitive to pertussis toxin and independent of protein kinase A (PKA) [31].

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

• Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function [25].
• Conversely, following HC exposure, the GR was downregulated and AhR levels were elevated [33].
• The absence of GR in the host cell line allows the selective analysis of transcription activation by aldosterone in cells expressing MR transiently [34].
• Northern analysis suggests that the CORT-GR signal transduction pathway modulates the rate of morphogenesis by regulating TGF-beta 2 and TGF-beta 3 mRNA expression [35].
• This hypothesis was tested using explant cultures derived from the GR-/- transplants in which the mineralocorticoid fludrocortisone was able to synergistically induce beta-casein gene expression in the presence of prolactin and insulin [21].

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

• By expressing green fluorescent protein (GFP)-tagged receptors and assessing subcellular localization in living cells by confocal microscopy, we have investigated the structural basis for the differential localization of GR and PR [36].
• To study the role of glucocorticoid receptor (GR) at different stages of mammary gland development, mammary anlage were rescued from GR-/- mice by transplantation into the cleared fat pad of wild-type mice [21].
• These different transcriptional activities of GR play an important role in glucocorticoid-mediated immunosuppression [38].
• Craniofacial tissues were collected from the embryos on GD14 and examined for AhR and GR expression using in situ hybridization [33].
• 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 [39].

References