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MGP001326

UniProt Annotations

Entry Information
Gene Namenuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Protein Entry
UniProt ID
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing, Alternative initiation; Named isoforms=10; Comment=At least 4 isoforms, Alpha (shown here), Alpha-B, Beta and Beta-B, are produced by alternative initiation at Met-1 and Met-27. The existence of isoform Alpha and isoform Alpha-B has been proved by mutagenesis. As the sequence environment of the 2 potential ATG initiator codons is the same for the other alternatively spliced isoforms, alternative initiation of translation could also occur on these transcripts. Additional isoforms seem to exist. {ECO:0000269|PubMed:11435610, ECO:0000269|PubMed:15265776}; Name=Alpha; Synonyms=Alpha-A; IsoId=P04150-1; Sequence=Displayed; Note=Predominant physiological form. Isoform Alpha-B is produced by alternative initiation at Met-27 of isoform Alpha. Both isoforms exhibit similar subcellular location and nuclear translocation after ligand activation. Isoform Alpha-B appears to be more susceptible to degradation, at least when expressed in mammalian cells, but more effective in transcriptional activation and not in transrepression.; Name=Beta; Synonyms=Beta-A; IsoId=P04150-2; Sequence=VSP_003703; Note=No hormone-binding activity. Widely expressed at low level.; Name=Alpha-2; Synonyms=Gamma; IsoId=P04150-3; Sequence=VSP_007363; Note=Due to a partial intron retention. Lower transcriptional activity. Expressed at low level.; Name=Beta-2; IsoId=P04150-6; Sequence=VSP_007363, VSP_003703; Note=Due to a partial intron retention.; Name=GR-A alpha; IsoId=P04150-5; Sequence=VSP_013340; Note=Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant myeloma patients.; Name=GR-A beta; IsoId=P04150-7; Sequence=VSP_013340, VSP_003703; Note=Lacks exons 5, 6 and 7.; Name=GR-P; IsoId=P04150-4; Sequence=Not described; Note=Encoded by exons 2-7 plus several basepairs from the subsequent intron region. Lacks the ligand binding domain. Accounts for up to 10-20% of mRNAs.; Name=Alpha-B; Synonyms=Beta-B; IsoId=P04150-8; Sequence=VSP_018773; Note=Produced by alternative initiation at Met-27 of isoform Alpha. Both isoforms exhibit similar subcellular location and nuclear translocation after ligand activation. Isoform Alpha-B appears to be more susceptible to degradation, at least when expressed in mammalian cells, but more effective in transcriptional activation and not in transrepression.; Name=Beta-B; IsoId=P04150-9; Sequence=VSP_018773, VSP_003703; Note=Produced by alternative initiation at Met-27 of isoform Beta.; Name=10; Synonyms=hGRDelta313-338; IsoId=P04150-10; Sequence=VSP_043908;
DiseaseGlucocorticoid resistance (GCRES) [MIM:138040]: Hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseGlucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainComposed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. {ECO:0000269|PubMed:3841189}.
FunctionReceptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21664385}.
InteractionP31749:AKT1; NbExp=5; IntAct=EBI-493507, EBI-296087; P59598:Asxl1 (xeno); NbExp=2; IntAct=EBI-493507, EBI-5743705; Q03135:CAV1; NbExp=2; IntAct=EBI-493507, EBI-603614; P01730:CD4; NbExp=2; IntAct=EBI-493507, EBI-353826; P00533:EGFR; NbExp=2; IntAct=EBI-493507, EBI-297353; Q6ZU52:KIAA0408; NbExp=2; IntAct=EBI-493507, EBI-739493; P06239:LCK; NbExp=3; IntAct=EBI-493507, EBI-1348; Q62667:Mvp (xeno); NbExp=2; IntAct=EBI-493507, EBI-918333; P82094:TMF1; NbExp=3; IntAct=EBI-493507, EBI-949763;
MiscellaneousCan up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from AR and HD through specific regulation of gene expression. Aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by this receptor, a well-characterized transcriptional regulator.
MiscellaneousHigh constitutive expression of isoform Beta by neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death. Up-regulation by proinflammatory cytokines such as IL8 further enhances their survival in the presence of glucocorticoids during inflammation.
PolymorphismCarriers of the 22-Glu-Lys-23 allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than non-carriers, resulting in a better metabolic health profile. Carriers have a better survival than non-carriers, as well as lower serum CRP levels. The 22-Glu-Lys-23 polymorphism is associated with a sex- specific, beneficial body composition at young-adult age, as well as greater muscle strength in males.
PtmAcetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity. {ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21980503}.
PtmIncreased proteasome-mediated degradation in response to glucocorticoids.
PtmPhosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid. The Ser- 203-phosphorylated form is mainly cytoplasmic, and the Ser-211- phosphorylated form is nuclear. Transcriptional activity correlates with the amount of phosphorylation at Ser-211. May be dephosphorylated by PPP5C, attenuates NR3C1 action. {ECO:0000269|PubMed:12000743, ECO:0000269|PubMed:18669648}.
PtmSumoylated; this reduces transcription transactivation. {ECO:0000269|PubMed:12144530}.
PtmUbiquitinated; restricts glucocorticoid-mediated transcriptional signaling. {ECO:0000250}.
SimilarityBelongs to the nuclear hormone receptor family. NR3 subfamily. {ECO:0000305}.
SimilarityContains 1 nuclear receptor DNA-binding domain. {ECO:0000255|PROSITE-ProRule:PRU00407}.
Subcellular LocationCytoplasm {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Mitochondrion. Nucleus {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Note=Cytoplasmic in the absence of ligand, nuclear after ligand- binding.
Subcellular LocationIsoform Beta: Nucleus. Note=Localized largely in the nucleus.
SubunitHeteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID, STIP1, or the immunophilin homolog PPP5C. Upon ligand binding FKBP5 dissociates from the complex and FKBP4 takes its place, thereby linking the complex to dynein and mediating transport to the nucleus, where the complex dissociates. Directly interacts with UNC45A. Binds to DNA as a homodimer, and as heterodimer with NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B homodimers and heterodimers. Interacts with NRIP1, POU2F1, POU2F2 and TRIM28. Interacts with several coactivator complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) and p160 coactivators such as NCOA2 and NCOA6. Interaction with BAG1 inhibits transactivation. Interacts with HEXIM1, PELP1 and TGFB1I1. Interacts with NCOA1, NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1. Interacts with CLOCK, CRY1 and CRY2 in a ligand- dependent fashion. Interacts with CIART. Interacts with RWDD3. Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3. Interacts with GRIP1 (PubMed:15769988). {ECO:0000269|PubMed:10477749, ECO:0000269|PubMed:10866662, ECO:0000269|PubMed:12151000, ECO:0000269|PubMed:12415108, ECO:0000269|PubMed:12686538, ECO:0000269|PubMed:15211577, ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:15941832, ECO:0000269|PubMed:16478993, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21730050, ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:9154805, ECO:0000269|PubMed:9590696}.
Tissue SpecificityWidely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. {ECO:0000269|PubMed:10902803}.
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/nr3c1/";
Web ResourceName=Wikipedia; Note=Glucocorticoid receptor entry; URL="http://en.wikipedia.org/wiki/Glucocorticoid_receptor";
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