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NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor)

Written2015-02Thomas D. Siamatras, Constantine A. Stratakis
Section on Endocrinology, Genetics(SEGEN), Program on Developmental Endocrinology, Genetics, Eunice Kennedy Shriver National Institute of Child Health, Human Development(NICHD), NIH, Bethesda, Maryland 20892, USA thomas.siamatras@mail.nih.gov; stratakc@mail.nih.gov

Abstract NR3C1 gene encodes the human glucocorticoid receptor(hGR), which is a ligand-dependent transcription factor and activates transcription of glucocorticoid-responsive genes through binding directly to glucocorticoid response elements(GREs) in their promoter region, or modulating transcriptional activity of other transcription factors through protein-protein interactions. hGR is implicated in a broad spectrum of biochemical physiologic functions, which are essential for life, and has also a key role in the maintenance of basal and stress-related homeostasis. Almost 20% of the genes expressed in human leukocytes are regulated positively or negatively by the hGR. Approximately every cellular, molecular and other physiologic network in the human body are influenced by this receptor and more specifically growth, reproduction, intermediary metabolism, immune and inflammatory reactions, as well as central nervous system and cardiovascular functions and lymphoproliferative disorders, cellular proliferation and differentiation in target tissues and normal renal tubular function and thus water and electrolyte homeostasis are only some of the examples where hGR is implicated(Nicolaides, Galata, Kino, Chrousos, and Charmandari, 2010).

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Identity

Alias_namesGRL
nuclear receptor subfamily 3, group C, member 1
nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Alias_symbol (synonym)GR
Other aliasGCCR
GCR
HGNC (Hugo) NR3C1
LocusID (NCBI) 2908
Atlas_Id 45665
Location 5q31.3  [Link to chromosome band 5q31]
Location_base_pair Starts at 143277931 and ends at 143403689 bp from pter ( according to hg19-Feb_2009)  [Mapping NR3C1.png]
 
  Figure 1. Human hGR/NR3C1 gene 5' Flanking Region
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
GNA13 (17q24.1) / NR3C1 (5q31.3)LRRFIP1 (2q37.3) / NR3C1 (5q31.3)NR3C1 (5q31.3) / ARHGAP26 (5q31.3)
NR3C1 (5q31.3) / HMHB1 (5q31.3)NR3C1 (5q31.3) / NR3C1 (5q31.3)NR3C1 (5q31.3) / RBM22 (5q33.1)
WNK1 (12p13.33) / NR3C1 (5q31.3)YIPF5 (5q31.3) / NR3C1 (5q31.3)

DNA/RNA

 
  Fig. 2ALPHA Genomic structure of the human glucocorticoid receptor (hGR/NR3C1) gene. It is composed of 9 exons. Alternative splicing of the primary transcript leads to the consequent two mRNA and proteins isoforms, hGRalpha and hGRbeta.
Description The human NR3C1 gene spans a length of 157,582 bases. The NR3C1 structural gene is composed of nine exons and is located in chromosome 5 (5q31.3)(Hollenberg et al., 1985)(Figure 2A).
Transcription The NR3C1 gene expresses mainly two mRNAs through alternative use of exons 9alpha and 9beta, producing two highly homologous receptor isoforms, termed alpha and beta(N. Z. Lu and Cidlowski, 2005). They are identical through amino acid 727, with hGRalpha having an additional 50 amino acids and hGRbeta having an extra no homologous 15 amino acids (Fig. 2A). Their molecular weights of hGR9alpha and hGR9beta are 97 and 94 kDa, respectively. Except these products, the NR3C1 gene expresses GR? (gamma), which has one amino acid insertion due to splicing variation at exon 3-4 boundary,(Meijsing et al., 2009) and GR-P isoform, which has only 676 amino acids and is encoded by an mRNA expressed from exons 1-7, but lacking exons 8 and 9 and unknown biologic significance(Hagendorf et al., 2005). The human GR gene has eleven different promoters with their alternative first exons (1A1, 1A2, 1A3, 1B, 1C, 1D, 1E, 1F, 1H, 1I and 1J) (Figure 1). Therefore, the human GR gene can produce eleven different transcripts alternating the different promoters that encode the same GR proteins having a common exon 2, which contains the translating ATG codon. 1A1, 1A2, 1A3 and 1I are located in the distal promoter region spanning ~32,000-36,000 bps upstream of the translation initiation site, while 1B, 1C, 1D, 1E, 1F, 1H and 1J position in the proximal promoter region located upstream up to ~5,000 bps. Alternate use of these promoters, differentiate the levels of GR protein isoforms in various tissues(Presul, Schmidt, Kofler, and Helmberg, 2007). Different splicing and translational GR isoforms originating from alternate promoters constitute up to 256 different combinations of homo- and hetero-dimers with different expression levels and transcriptional activities. This marked diversity in the transcription/translation of the GR gene allows cells/tissues to accommodate appropriately to the circulating concentrations of glucocorticoids depending on their needs(Chrousos and Kino, 2005a) and is responsible for the highly stochastic nature of the glucocorticoid-signaling pathway (Chrousos and Kino, 2005b).
Pseudogene The NR3C1 gene has a pseudogene (NC3C1P1) in chromosome 16q (provided by RefSep 2012)

Protein

 
  Fig 2B Functional domains of the NR3C1/hGRalpha. AF, activation function; DBD, DNA-binding domain; HSPs, heat shock proteins; LBD, ligand-binding domains; NLS, nuclear localization signal.
Description The human NR3C1 protein sequence (NP_000167.1)consists of 777 amino acids and has a MW of 85659 Da. Without the presence of the ligand, hGRalpha takes part in a heteromultimeric cytoplasmic complex with chaperone Heat Shock Proteins (HSP)90,70,50 immunophilins and other proteins. As soon as it binds to the ligand, dissociates from the previous complex and FK506-binding immunophilin heat shock protein 56 takes its place, thereby connecting to dynein and mediating the transportation to the nucleus, where it dissociates(Czar, Lyons, Welsh, Renoir, and Pratt, 1995). When it reaches the nucleus, the receptor binds as a homodimer to various Glucocorticoid Response Elements(GREs) sequences in the promoter region of many genes, and as a heterodimer with NR3C2 or the retinoid X receptor, thus regulating their expression either positively or negatively depending on GRE sequence and promoter context. The ligand-activated hGRalpha modulates gene expression without binding to GREs, by interracting also with other transcription factors, such as activator protein-1(AP-1), nuclear factor-?B(NF-?B), p53 and signal transducers and activators of transcription(STATs). For the transcription when hGRalpha uses its transcriptional activation domains, AF-1 and AF-2, as surfaces to interact with specific nuclear receptor coactivators and chromatin-remodeling complexes, then these coactivators form a bridge between DNA-bound hGRalpha and the transcription initiation complex, conveying the transmission of the glucocorticoid signal to the RNA polymerase II and its ancillary components leading to initiation and promotion of the transcription. As a member of the nuclear receptor superfamily, hGR has 3 major domains: the N-terminal domain (NTD), middle DNA-binding domain (DBD) and the C-terminal ligand-binding domain (LBD) as illustrated in(Fig. 2B). Using the typical nomenclature for NR subdomains, hGR consists of the amino-terminal A/B region (corresponding to NTD), C (DBD), D (hinge region) and E (LBD) regions, without having the F region. The N-terminal domain (NTD) consist of transactivation domain, termed activation function (AF)-1, located between amino acids 77 and 262, activated when is ligand-independent. It has an important role in the interaction of the receptor with molecules necessary for stimulation of transcription, such as coactivators, chromatin modulators and basal transcription factors. The DNA-binding domain (DBD) consists of amino acids 420-480, contains two zinc finger motifs through which binds to specific DNA sequences, such as the glucocorticoid response elements (GREs) in the promoter region(s) of specific genes. The DBD also contains sequences important for receptor dimerization and nuclear translocation. The hinge region gives flexibility connecting DBD with LBD by conferring structural flexibility in the receptor dimers, allowing single receptor dimmer to interact with multiple GREs and different sequences. The ligand-binding domain (LBD) consist of amino acids 481-777, binds ligand glucocorticoid with its ligand-binding pocket and contains a second transactivation domain, the ligand-depended AF-2 which plays an important role in the glucocorticoid-induced stimulation of hGR transcriptional activity, by interacting with coactivators containing LxxLL motifs. LBD takes part in the complex formation with heat shock proteins, in the process of nuclear translocation and receptor dimerization(Nicolaides, et al., 2010).
Expression Ubiquitous. Almost all human tissues and cells are expressing the hGRalpha. The GR expression has been reported in the Bone Marrow, Monocytes, Dendritic Cells, NK Cells, T Cells (CD4+), T Cells (CD8+), B Lymphoblasts, B Cells, Lymph Node, Spleen, Thymus, Retina, Heart, Cardiac Myocytes, Atrioventricular Node, Smooth Muscle, Skeletal Muscle, Appendix, Pancreatic Islet, Small Intestine, Colon, Adipocyte, Kidney, Liver, Lung, Trachea, Bronchial Epithelium, Tongue, Thyroid, Salivary Gland, Adrenal Gland, Breast, Skin, Ovary, Uterus Corpus, Uterin Cervix, Placenta, Fetal Brain, Liver, Lung and thyroid, Tonsil, Prefrontal Cortex, Cingulate Cortex, Parietal Lobe, Temporal Lobe, Occipital Lobe, Ciliary Ganglion, Globus Pallidus, Olfactory Bulb, Thalamus, Hypothalamus, Subthalamic Nucleus, Caudate Nucleus, Amygdala, Pons, Medulla Oblongata, SupCervical Ganglion, Dorsal Root Ganglion, Trigeminal Ganglion, Spinal Cord, Pineal (Day)and Pineal (Night), Pituitary, Prostate, Testis Germ, Testis Intersitial, Testis Leydig cells.
Localisation In the absence of ligand, hGRalpha resides mostly in the cell cytoplasm, but upon ligand-induced activation, the receptor dissociates from the multiprotein complex and translocate into the nucleus. After binding to specific DNA responsive elements remains within the nucleus for a considerable length of time and is then exported to the cytoplasm. It is also present in the Mitochondrion and Plasma membrane. The isoform Beta is mainly expressed in the nucleus.
Function hGR has a dual mode of transcriptional activity: acting either as a glucocorticoid-dependent transcription factor, binding mainly to glucocorticoid response elements (GRE) or functioning as a modulator of other transcription factors through protein-protein interaction. Post-translational modifications (PTMs), such as phosphorylation, acetylation, ubiqutilation and nitrosylation, play also an important role in the regulation of GR activity, affecting the receptor stability, subcellular localization, and also interaction between GR and other proteins, influencing finally the transcriptional activity. Recent studies have demonstrated that the circadian rhythm transcription factors CLOCK and BMAL1 repress GR-induced transcriptional activity by acetylating several lysine residues(Kino and Chrousos, 2011).
Homology Is a member of the nuclear hormone receptor family, NR3 subfamily.

Mutations

Note Mutations or polymorphisms in the hGR gene impair one or more of the molecular mechanisms of hGRalpha action and as a final consequence alter the tissue sensitivity to glucocorticoids. Reduced affinity of the mutant receptors for the ligand, altered subcellular localization, delayed nuclear translocation after binding to the ligand, reduced ability to bind with GREs and decreased transcriptional activity, altering the exertion of a dominant negative effect upon the wild-type receptor, reduced interaction with other coactivators and reduced motility within the nucleus are some of the mechanisms of mutant hGR(Charmandari, Chrousos, and Kino, 2009). Although, most mutations of the NR3C1 gene exert generalized glucocorticoid resistance there is one mutation reported to date in the hGRalpha NTD region that replaces aspartic acid at amino acid 401 by histidine (D401H) facilitating the mediated gene expression(Charmandari et al., 2008). Interindividual variations in tissue sensitivity to glucocorticoids have been described within the normal population and are mainly attributed to polymorphisms in the hGR gene. A heterozygous polymorphism replacing aspartic acid to serine at amino acid 363 mildly increases transcriptional activity, and arginine to lysine replacement at amino acid 23 is associated with relative glucocorticoid resistance. A single nucleotide polymorphism that replaces A with G at the nucleotide 3669(A3669G) located in the 3' end of exon 9beta increases the stability of GRbeta mRNA, leading to greater inhibition of GRalpha-induced transcriptional activity and thus glucocorticoid resistance(Syed et al., 2006).
It is worth mentioning also the fact that there is a plethora of laboratory generated mutated GR proteins, which provides an interesting tool for exploring hGR structure-function relationships. (Beck, De Bosscher, and Haegeman, 2011)
 
  Table 1: Reported mutations in the hGR/NR3C1 gene causing either generalized glucocorticoid resistance or increased sensitivity.

Implicated in

Note
  
Entity Normal physiology and homeostasis
Note The stochastic nature of glucocorticoid signaling pathways(Chrousos and Kino, 2005b), and the variable effect that hGR gene mutations/polymorphisms exert on glucocorticoid signal transduction, suggest that alterations in hGR action affect many critical biological processes including the behavioural and physiologic responses to stress, the immune and inflammatory reaction, the process of sleep, growth and reproduction. It is an extremely important component of many cellular and molecular signaling pathways in maintaining homeostasis and preserving normal physiology(Charmandari and Kino, 2010)
  
  
Entity Primary MyeloFibrosis(PMF)
Note The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor is increased in patients with polycythemia vera compared to normal population. This variant allele at the homozygous state (G/G) is considered also a susceptibility allele to PMF. Especially, in cooperation with other mutated genes such as JAK2V617F, the glucocorticoid receptor A3669G SNP contributes to the phenotype of excess myeloproliferation, and determination of Blast Transformation(Poletto et al., 2012).
  
  
Entity Acute Lymphoblastic Leukemia (ALL)
Note Glucocorticoids (GC) are pivotal in the treatment of acute lymphoblastic leukemia (ALL) and other lymphoid malignancies, since they induce apoptosis in lymphoblasts. Although research studies delineated the transcriptional response to GCs in two ALL cell lines (precursor B-ALL and T-childhood ALL), forming mainly the basis for the molecular understanding of their antileukemic (and perhaps other) effects; questions on their induction of apoptosis and cell cycle arrest in leukemic cell lines studied still exists. Although a wide range of possible interacting genes were analysed( c-myc and Cyclin D3, BMF, MCL1, Bcl-XL, PMAIP1/Noxa, ZBTB16, SLA, PFKFB2, TNFAIP8, GPR65/TDAG8,DDIT4/Dig2, MAP2K3, MYC, mir17~92, TXNIP) indications were that they had only moderate influence if any, on GC-induced apoptosis in the experimental systems mentioned with the only exception of members of the BCL2 gene family. Could it be a single critical gene downstream responsible for the GR apoptosis induction or rather a GC-regulated network of genes; this is still under investigation(Rainer et al., 2012). However, GC-resistance is major therapeutic problem without yet a clear molecular mechanism. In two key models of acute lymphoblastic leukemia the GCs resistance was associated with mutations at the level of the glucocorticoid receptor (some of which were newly identified; previously not associated with GC resistance, such as: A484D, P515H, L756N, Y663H, L680P, and R714W0(Schmidt et al., 2006). The survival probabilities in children with ALL were associated with homozygocity of G allele of the NR3C1 BcII polymorphism, presenting a worse progression and prognosis of the disease(Fleury et al., 2004), and also three other NR3C1 SNPs polymorphism; ?627A/G, intron2 +646)C/T and 9bT/C were associated with dismal childhood cALL outcome with reduced event-free and overall survival (Labuda et al., 2010)
  
  
Entity Multiple Myeloma
Note Downregulation of GR mRNA in a glucocorticoid resistant Multiple Myeloma cell line is in partly explained by the transcriptional block at intron B of NR3C1(Sanchez-Vega and Gandhi, 2009). Novel Glucocorticoid-based therapy based on combination of selective glucocorticoid receptor (GR) activators (SEGRA) and proteasome inhibitors are effective in the treatment of Multiple Myeoloma, circumventing the undesired effects of chronic use of glucocorticosteroids. The novel non-steroidal GR modulator Compound A (CpdA) retains glucocorticoid-like anti-inflammatory and anti-cancer activity and has fewer side effects compared to glucocorticoids. (Sommer and Ray, 2008) CpdA strongly inhibits growth and viability of multiple myeloma cells in GR-dependent manner. There is evidence for an important GR-dependent cooperation between CpdA and proteasome-inhibitor Bortezomib in eliminating survival of multiple myeloma cells(Lesovaya et al., 2013).
  
  
Entity Osteosarcoma (OS)
Note Osteoblasts are highly sensitive to glucocorticoids, which reduce their proliferation and show apoptosis upon glucocorticoid treatment. In contrast to normal osteoblasts, OS cells express 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts cortisol (active) to cortisone (inactive), and thus, expression of 11beta-HSD2 renders OS cells resistant to glucocorticoids and subsequent apoptosis. High 11beta-HSD2 expression is correlated with a poor response to GCs treatment in Osteosarcoma(Patel et al., 2012).
  
  
Entity Prostate Cancer
Note Glucocorticoids are used in clinical practise for patients with hormone-refractory prostate cancer. They inhibit tumour angiogenesis and subsequent tumour growth, possibly by down-regulating vascular endothelial growth factor (VEGF) and interleukin-8 and additionally supressing tumour-associated lymphangiogenesis by down-regulating VEGF-C through glucocorticoid receptor(Yano et al., 2006).
  
  
Entity Ectopic ACTH-producing tumours
Note Non-pituitary (ectopic) ACTH secretion generally is not responding to exogenous glucocorticoid administration. DMS-79 small-cell lung carcinoma cells derived from these ectopic ACTH-producing tumours express an abnormal GR mRNA which encodes a protein lacking the steroids-binding domain leading to misfunctional characteristics of this ligand-activated transcription factor. The abnormal transcripts in these cells arrived from normal GR genes by aberrant splicing of intron G (between exons 7 and 8). Although GR signalling defects seem likely to cause glucocorticoid resistance of non-pituitary tumours, the suppression at high doses of exogenous glucocorticoids as is appeared particularly in bronchial carcinoids implicates other potential mechanisms are also possible(Parks, Turney, Detera-Wadleigh, and Kovacs, 1998). Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC). High levels of hGR in patients with advanced NSCLC are associated with better outcome(Y. S. Lu et al., 2006). GR expression causes activation of the apoptotic pathway as evidenced by marked induction of caspase-3 activity. On the other hand methylation analysis revealed that there was significantly increased DNA methylation in the 1C promoter of the NR3C1, which was negatively correlated with GR protein expression in tested human SCLC cells(Kay et al., 2011).
  
  
Entity Pituitary Adenoma and Adrenocortical tumours
Note The expression of the GR is an essential element of the negative closed feedback loop formed by corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol in the context of the hypothalamic-pituitary-adrenal (HPA) axis. The variability in expression and function of the GR in pituitary and adrenocortical cells is responsible for the considerable differences in function of this loop. Some of the variation can be ascribed to functional GR polymorphism, which may also predispose to adrenocortical tumour formation(Majnik et al., 2006). This variability may explain why it is so difficult to interpret (or reproduce) results regarding the analysis of diagnostic testing of the HPA axis in patients with pituitary adenomas (Cushing disease) or adrenocortical tumours (Cushing syndrome). (Briassoulis, Damjanovic, Xekouki, Lefebvre, and Stratakis, 2011)
  
  
Entity Astrocytoma
Note Glial tumour cells are sensitive to glucocorticoids (GC), which cross the blood-brain barrier and are used for certain glial tumours treatment. Although low-grade malignant human astrocytoma cells did not present a significant hGRalpha expression they did endogenously express the Cortisol Binding Globulin (CBG). Upon GCs treatment CBG is immediately released (possibly in a nongenomic way) suggesting the apoptosis of certain glial tumours is partly associated with this phenomenon of CBG-release and not through hGR(Pusch, Wegmann, Caldwell, and Jirikowski, 2009)
  
  
Entity Sarkoma Kaposi(KS)
Note Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)-KS cells expressed unusually high levels of glucocorticoid receptor protein and at the same time were significantly stimulated by glucocorticoids(Enwonwu, 1996). The increased expression of functional GRs was associated with four cytokines, namely interleukin-1beta, interleukin-6, tumour necrosis factor-alpha, and oncostatin M, all of which are known autocrine growth factors for AIDS-KS cells. The high levels of GR expression in these cells and the up-regulation of GRs by KS-growth-promoting factors are associated with the enhanced and sustained sensitivity to the actions of glucocorticoids(Guo et al., 1996).
  
  
Entity Cancers of the Digestive System
Note GR is strongly expressed in oesophageal squamous epithelia, pancreatic islet cells and hepatocytes, but generally it has a weak or negative expression in non-squamous epithelia (gastric and colorectal adenocarcinomas). Chemotherapy resistance in tumours originating from the above mentioned tumour-cells induced by the use of Dexamethasone (DEX) is suggesting that GR expression may be biologically important in some GR-expressing carcinomas(Lien et al., 2008). In Gastric Carcinoma, NR3C1 methylation was a useful marker for identifying distinct type-subsets of these carcinomas(Kang et al., 2008). Analysis of tissues sections in well differentiated pancreatic adenocarcinomas revealed a strong positivity (mainly cytoplasmic) for Glucocorticoid receptor, but interestingly the liver metastasis of these tumours was completely negative(Bekasi and Zalatnai, 2009).
  
  
Entity Colorectal cancer
Note A significant difference in mRNA expression (reduced) of hGRalpha, 11beta-HSD-1(overexpressed) and other glucocorticoid metabolism-related genes was observed in colorectal adenocarcinomas which were associated with the downregulation of E-cadherin mRNA, a critical required step in the progress of tumor invasiveness, connecting these genes to carcinogenesis and progression of colorectal cancer(Storkson et al., 2012). Cancer-specific hypermethylation of the NR3C1 gene was identified in colorectal tumors(Lind et al., 2006) and FK506-binding proteins(FKBPS) suppressed the proliferation of colorectal adenocarcinoma possibly due to the suppression of function of the glucocorticoid receptor(Mukaide et al., 2008).
  
  
Entity Cervical Cancer
Note GR expression is observed in cervical low and high-grade intraepithelial neoplasia and in invasive cervical squamous cell carcinoma. Since glucocorticoids act also as cofactor with human papillomaviruses in the etiology of cervical cancer, and inhibit chemotherapy or radiation-induced apoptosis, the persistence of GR in cervix cancer cells questions the combined use of glucocorticosteroids with antineoplastic drugs or other agents in clinical practise settings for women presenting with cervix cancer. (Buxant, Bucella, Anaf, Simon, and Noel, 2009)
  
  
Entity Breast cancer
Note Glucocorticoid receptor (GR) is playing an important role in mammary gland development and differentiation, and has been implicated in breast tumourigenesis without actually knowing the exact biochemical pathways or consequence of this unique expression of GR in terms of progression of Breast Cancer. It is strongly expressed in metaplastic carcinomas and malignant phyllodes tumour but there is lack of important GR expression in great majority of non-metaplastic carcinomas(Lien et al., 2006). Glucocorticoid Receptor and Nuclear Factor Nf?BETA signaling pathways appears to be an important phenomenon in the initiation, progression and recurrence of inflammatory Breast Cancer (BC), wherein NFkB and glucocorticoid receptor (GR) are critical transcription factors in regulating inflammation. NFkB is generally pro-inflammatory, while GR is anti-inflammatory. It is the crosstalk between these two transcription factors that exert a crucial function in determining the survival or apoptosis of BC cells. However, the use of Glucocorticosteroids (GCs) and their biological effects through GR unexpectedly promote cancer cell survival and induce chemo-resistance in BC(Ling and Kumar, 2012). Curcumin which exerts a wide spectrum of anti-inflammatory, anti-oxidant and anti-cancer activities is under investigation as chemopreventive and chemotherapeutic agent which main action is through GR and NF?B modificatory expressions(Sinha, Biswas, Sung, Aggarwal, and Bishayee, 2012).
  
  
Entity Coronary Artery Disease
Note Development of Epicardial Adipose Tissue is not augmented by glucocorticoids, as does the Subcutaneous Adipose Tissue. The decreased total GR mRNA expression and reduced associated transcripts in promoter B and C into this specific tissue; suggest a protective role for Coronary physiology(Silaghi, Silaghi, Scridon, Pais, and Achard, 2012)
  
  
Entity Bronchial asthma
Note The N363S single nucleotide polymorphisms (SNPs) of the hGR/NR3C1 gene are supposed to play an important role in the development of bronchial asthma and in the alteration of sensitivity to Glucocorticosteroids in severe bronchial asthma (Panek et al., 2012). At the cellular level the impairment of GR-Ser211 phosphorylation in Airway Smooth Muscle cells by proasthmatic cytokines drastically reduced their responsiveness to glucocorticoids(Bouazza et al., 2012) and the use of glucocorticoid Dexamethasone repressed the production of mucin glycoproteins in lung epithelial cancer cells. This repression is induced by lower expression of mucin genes, which is mediated by the glucocorticoid receptor (GR) and two glucocorticoid response elements (GREs) in the mucin gene promoter region(Chen et al., 2012).
  
  
Entity Adult Onset Chronic Diseases
Note Extreme maternal psychosocial stressors and early life experiences in utero and in newborns modify locus-specific epigenetic marks in the newborn correlating these events with the newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation impairs plasticity in subsequent NR3C1 gene expression and accordingly the range of future stress adaptation responses, resulting possibly in increased risk for adult-onset diseases(Mulligan, D'Errico, Stees, and Hughes, 2012).
  
  
Entity Rheumatic Diseases
Note The specific actions of the hGR appear to play an important role in the regulation of the immune system and consequently play a specific role in diseases such as Rheumatoid arthritis, Systemic Lupus erythematosus, and ankylosing spondylitis. It is the splicing isoform GRbeta which is highly expressed in these patients that exert a negative effect on GRalpha and leads to resistance to glucocorticoids. Proinflammatory cytokines and the presence of a single nucleotide polymorphism in the 3' untranslated region of the hGRbeta mRNA(rs6198G allele) are responsible for the increased presence of the splicing variant GRbeta(Kino, Charmandari, and Chrousos, 2011).
  

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ADAMTS1, CRABP1, and NR3C1 identified as epigenetically deregulated genes in colorectal tumorigenesis
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Cell Oncol 2006;28(5-6):259-72
PMID 17167179
 
Crosstalk between NFkB and glucocorticoid signaling: a potential target of breast cancer therapy
Ling J, Kumar R
Cancer Lett 2012 Sep 28;322(2):119-26
PMID 22433713
 
Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes
Lu NZ, Cidlowski JA
Mol Cell 2005 Apr 29;18(3):331-42
PMID 15866175
 
Glucocorticoid receptor expression in advanced non-small cell lung cancer: clinicopathological correlation and in vitro effect of glucocorticoid on cell growth and chemosensitivity
Lu YS, Lien HC, Yeh PY, Kuo SH, Chang WC, Kuo ML, Cheng AL
Lung Cancer 2006 Sep;53(3):303-10
PMID 16806572
 
Overrepresentation of the N363S variant of the glucocorticoid receptor gene in patients with bilateral adrenal incidentalomas
Majnik J, Patocs A, Balogh K, Toth M, Gergics P, Szappanos A, Mondok A, Borgulya G, Panczel P, Prohaszka Z, Racz K
J Clin Endocrinol Metab 2006 Jul;91(7):2796-9
PMID 16636127
 
DNA binding site sequence directs glucocorticoid receptor structure and activity
Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Yamamoto KR
Science 2009 Apr 17;324(5925):407-10
PMID 19372434
 
FKBP51 expressed by both normal epithelial cells and adenocarcinoma of colon suppresses proliferation of colorectal adenocarcinoma
Mukaide H, Adachi Y, Taketani S, Iwasaki M, Koike-Kiriyama N, Shigematsu A, Shi M, Yanai S, Yoshioka K, Kamiyama Y, Ikehara S
Cancer Invest 2008 May;26(4):385-90
PMID 18443959
 
Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight
Mulligan CJ, D'Errico NC, Stees J, Hughes DA
Epigenetics 2012 Aug;7(8):853-7
PMID 22810058
 
The human glucocorticoid receptor: molecular basis of biologic function
Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E
Steroids 2010 Jan;75(1):1-12
PMID 19818358
 
The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1 gene in patients with bronchial asthma
Panek M, Pietras T, Antczak A, Fabijan A, Przemecka M, Górski P, Kuna P, Szemraj J
Int J Mol Med 2012 Jul;30(1):142-50
PMID 22469783
 
An ACTH-producing small cell lung cancer expresses aberrant glucocorticoid receptor transcripts from a normal gene
Parks LL, Turney MK, Detera-Wadleigh S, Kovacs WJ
Mol Cell Endocrinol 1998 Jul 25;142(1-2):175-81
PMID 9783913
 
Expression of 11-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments
Patel P, Hardy R, Sumathi V, Bartle G, Kindblom LG, Grimer R, Bujalska I, Stewart PM, Rabbitt E, Gittoes NJ, Cooper MS
Endocr Relat Cancer 2012 Jul 22;19(4):589-98
PMID 22719058
 
A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation
Poletto V, Rosti V, Villani L, Catarsi P, Carolei A, Campanelli R, Massa M, Martinetti M, Viarengo G, Malovini A, Migliaccio AR, Barosi G
Blood 2012 Oct 11;120(15):3112-7
PMID 22879541
 
Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor
Presul E, Schmidt S, Kofler R, Helmberg A
J Mol Endocrinol 2007 Feb;38(1-2):79-90
PMID 17242171
 
Expression of corticosteroid-binding globulin in human astrocytoma cell line
Pusch L, Wegmann S, Caldwell JD, Jirikowski GF
Cell Mol Neurobiol 2009 Jun;29(4):583-8
PMID 19172388
 
Research resource: transcriptional response to glucocorticoids in childhood acute lymphoblastic leukemia
Rainer J, Lelong J, Bindreither D, Mantinger C, Ploner C, Geley S, Kofler R
Mol Endocrinol 2012 Jan;26(1):178-93
PMID 22074950
 
Glucocorticoid resistance in a multiple myeloma cell line is regulated by a transcription elongation block in the glucocorticoid receptor gene (NR3C1)
Sánchez-Vega B, Gandhi V
Br J Haematol 2009 Mar;144(6):856-64
PMID 19133980
 
Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor
Schmidt S, Irving JA, Minto L, Matheson E, Nicholson L, Ploner A, Parson W, Kofler A, Amort M, Erdel M, Hall A, Kofler R
FASEB J 2006 Dec;20(14):2600-2
PMID 17077285
 
Glucocorticoid receptors in human epicardial adipose tissue: role of coronary status
Silaghi A, Silaghi H, Scridon T, Pais R, Achard V
J Endocrinol Invest 2012 Jul;35(7):649-54
PMID 21971518
 
Chemopreventive and chemotherapeutic potential of curcumin in breast cancer
Sinha D, Biswas J, Sung B, Aggarwal BB, Bishayee A
Curr Drug Targets 2012 Dec;13(14):1799-819
PMID 23140290
 
Novel therapeutic agents targeting the glucocorticoid receptor for inflammation and cancer
Sommer P, Ray DW
Curr Opin Investig Drugs 2008 Oct;9(10):1070-7
PMID 18821468
 
mRNA expression of adipocytokines and glucocorticoid-related genes are associated with downregulation of E-cadherin mRNA in colorectal adenocarcinomas
Størkson RH, Aamodt R, Vetvik KK, Pietilainen K, Bukholm G, Jonsdottir K, Vollan HS, Sonerud T, Lüders T, Jacobsen MB, Bukholm IR
Int J Colorectal Dis 2012 Aug;27(8):1021-7
PMID 22411584
 
Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women
Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Weaver JU
Obesity (Silver Spring) 2006 May;14(5):759-64
PMID 16855182
 
Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells
Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara K
Clin Cancer Res 2006 Oct 15;12(20 Pt 1):6012-7
PMID 17062674
 

Citation

This paper should be referenced as such :
Thomas D Siamatras, Constantine A Stratakis
NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor)
Atlas Genet Cytogenet Oncol Haematol. 2016;20(3):121-129.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NR3C1ID45665ch5q31.html


External links

Nomenclature
HGNC (Hugo)NR3C1   7978
Cards
AtlasNR3C1ID45665ch5q31
Entrez_Gene (NCBI)NR3C1  2908  nuclear receptor subfamily 3 group C member 1
AliasesGCCR; GCR; GCRST; GR; 
GRL
GeneCards (Weizmann)NR3C1
Ensembl hg19 (Hinxton)ENSG00000113580 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000113580 [Gene_View]  chr5:143277931-143403689 [Contig_View]  NR3C1 [Vega]
ICGC DataPortalENSG00000113580
TCGA cBioPortalNR3C1
AceView (NCBI)NR3C1
Genatlas (Paris)NR3C1
WikiGenes2908
SOURCE (Princeton)NR3C1
Genetics Home Reference (NIH)NR3C1
Genomic and cartography
GoldenPath hg38 (UCSC)NR3C1  -     chr5:143277931-143403689 -  5q31.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NR3C1  -     5q31.3   [Description]    (hg19-Feb_2009)
EnsemblNR3C1 - 5q31.3 [CytoView hg19]  NR3C1 - 5q31.3 [CytoView hg38]
Mapping of homologs : NCBINR3C1 [Mapview hg19]  NR3C1 [Mapview hg38]
OMIM138040   615962   
Gene and transcription
Genbank (Entrez)###############################################################################################################################################################################################################################################################
RefSeq transcript (Entrez)NM_000176 NM_001018074 NM_001018075 NM_001018076 NM_001018077 NM_001020825 NM_001024094 NM_001204258 NM_001204259 NM_001204260 NM_001204261 NM_001204262 NM_001204263 NM_001204264 NM_001204265
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NR3C1
Cluster EST : UnigeneHs.122926 [ NCBI ]
CGAP (NCI)Hs.122926
Alternative Splicing GalleryENSG00000113580
Gene ExpressionNR3C1 [ NCBI-GEO ]   NR3C1 [ EBI - ARRAY_EXPRESS ]   NR3C1 [ SEEK ]   NR3C1 [ MEM ]
Gene Expression Viewer (FireBrowse)NR3C1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2908
GTEX Portal (Tissue expression)NR3C1
Human Protein AtlasENSG00000113580-NR3C1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04150   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP04150  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP04150
Splice isoforms : SwissVarP04150
PhosPhoSitePlusP04150
Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
Domains : Interpro (EBI)Glcrtcd_rcpt    Nucl_hrmn_rcpt_lig-bd    Nuclear_hrmn_rcpt    Znf_hrmn_rcpt    Znf_NHR/GATA   
Domain families : Pfam (Sanger)GCR (PF02155)    Hormone_recep (PF00104)    zf-C4 (PF00105)   
Domain families : Pfam (NCBI)pfam02155    pfam00104    pfam00105   
Domain families : Smart (EMBL)HOLI (SM00430)  ZnF_C4 (SM00399)  
Conserved Domain (NCBI)NR3C1
DMDM Disease mutations2908
Blocks (Seattle)NR3C1
PDB (SRS)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
PDB (PDBSum)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
PDB (IMB)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
PDB (RSDB)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
Structural Biology KnowledgeBase1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
SCOP (Structural Classification of Proteins)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
CATH (Classification of proteins structures)1M2Z    1NHZ    1P93    3BQD    3CLD    3E7C    3H52    3K22    3K23    4CSJ    4HN5    4HN6    4LSJ    4MDD    4P6W    4P6X    4UDC    4UDD    5CBX    5CBY    5CBZ    5CC1    5EMC    5EMP    5EMQ   
SuperfamilyP04150
Human Protein Atlas [tissue]ENSG00000113580-NR3C1 [tissue]
Peptide AtlasP04150
HPRD00679
IPIIPI00022282   IPI00219946   IPI00251749   IPI01024920   IPI00604725   IPI00759700   IPI00759729   IPI01011884   IPI00978266   IPI00978393   IPI00977930   IPI00977002   IPI00976593   IPI00976066   IPI00555880   IPI00966619   
Protein Interaction databases
DIP (DOE-UCLA)P04150
IntAct (EBI)P04150
FunCoupENSG00000113580
BioGRIDNR3C1
STRING (EMBL)NR3C1
ZODIACNR3C1
Ontologies - Pathways
QuickGOP04150
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  core promoter binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  RNA binding  glucocorticoid receptor activity  steroid binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  mitochondrial matrix  microtubule organizing center  spindle  cytosol  transcription, DNA-templated  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  transcription initiation from RNA polymerase II promoter  apoptotic process  cell cycle  chromosome segregation  signal transduction  zinc ion binding  covalent chromatin modification  SUMO binding  glucocorticoid-activated RNA polymerase II transcription factor binding transcription factor activity  glucocorticoid receptor signaling pathway  protein complex  glucocorticoid mediated signaling pathway  positive regulation of transcription from RNA polymerase II promoter  cell division  Hsp90 protein binding  cellular response to steroid hormone stimulus  cellular response to dexamethasone stimulus  cellular response to transforming growth factor beta stimulus  steroid hormone binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  core promoter binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  RNA binding  glucocorticoid receptor activity  steroid binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  mitochondrial matrix  microtubule organizing center  spindle  cytosol  transcription, DNA-templated  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  transcription initiation from RNA polymerase II promoter  apoptotic process  cell cycle  chromosome segregation  signal transduction  zinc ion binding  covalent chromatin modification  SUMO binding  glucocorticoid-activated RNA polymerase II transcription factor binding transcription factor activity  glucocorticoid receptor signaling pathway  protein complex  glucocorticoid mediated signaling pathway  positive regulation of transcription from RNA polymerase II promoter  cell division  Hsp90 protein binding  cellular response to steroid hormone stimulus  cellular response to dexamethasone stimulus  cellular response to transforming growth factor beta stimulus  steroid hormone binding  
Pathways : BIOCARTAChromatin Remodeling by hSWI/SNF ATP-dependent Complexes [Genes]    NFkB activation by Nontypeable Hemophilus influenzae [Genes]    Visceral Fat Deposits and the Metabolic Syndrome [Genes]    Corticosteroids and cardioprotection [Genes]   
Pathways : KEGGNeuroactive ligand-receptor interaction   
REACTOMEP04150 [protein]
REACTOME PathwaysR-HSA-8849473 [pathway]   
NDEx NetworkNR3C1
Atlas of Cancer Signalling NetworkNR3C1
Wikipedia pathwaysNR3C1
Orthology - Evolution
OrthoDB2908
GeneTree (enSembl)ENSG00000113580
Phylogenetic Trees/Animal Genes : TreeFamNR3C1
HOVERGENP04150
HOGENOMP04150
Homologs : HomoloGeneNR3C1
Homology/Alignments : Family Browser (UCSC)NR3C1
Gene fusions - Rearrangements
Fusion : MitelmanGNA13/NR3C1 [17q24.1/5q31.3]  [t(5;17)(q31;q24)]  
Fusion : MitelmanNR3C1/HMHB1 [5q31.3/5q31.3]  [t(5;5)(q31;q31)]  
Fusion: TCGA_MDACCGNA13 17q24.1 NR3C1 5q31.3 LGG
Fusion: TCGA_MDACCNR3C1 5q31.3 HMHB1 5q31.3 GBM
Tumor Fusion PortalNR3C1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNR3C1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NR3C1
dbVarNR3C1
ClinVarNR3C1
1000_GenomesNR3C1 
Exome Variant ServerNR3C1
ExAC (Exome Aggregation Consortium)ENSG00000113580
GNOMAD BrowserENSG00000113580
Genetic variants : HAPMAP2908
Genomic Variants (DGV)NR3C1 [DGVbeta]
DECIPHERNR3C1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNR3C1 
Mutations
ICGC Data PortalNR3C1 
TCGA Data PortalNR3C1 
Broad Tumor PortalNR3C1
OASIS PortalNR3C1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNR3C1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNR3C1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NR3C1
DgiDB (Drug Gene Interaction Database)NR3C1
DoCM (Curated mutations)NR3C1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NR3C1 (select a term)
intoGenNR3C1
NCG5 (London)NR3C1
Cancer3DNR3C1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM138040    615962   
Orphanet8672   
DisGeNETNR3C1
MedgenNR3C1
Genetic Testing Registry NR3C1
NextProtP04150 [Medical]
TSGene2908
GENETestsNR3C1
Target ValidationNR3C1
Huge Navigator NR3C1 [HugePedia]
snp3D : Map Gene to Disease2908
BioCentury BCIQNR3C1
ClinGenNR3C1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2908
Chemical/Pharm GKB GenePA181
Clinical trialNR3C1
Miscellaneous
canSAR (ICR)NR3C1 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNR3C1
EVEXNR3C1
GoPubMedNR3C1
iHOPNR3C1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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