NR3C1

This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

Nuclear Receptor Subfamily 3 Group C Member 1

Receptor for glucocorticoids (GC) (PubMed:27120390).
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. Involved in chromatin remodeling (PubMed:9590696).
Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514).
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 (By similarity).
Isoform Alpha
Has transcriptional activation and repression activity (PubMed:15866175, PubMed:19248771, PubMed:20484466, PubMed:23820903, PubMed:11435610, PubMed:15769988, PubMed:17635946, PubMed:19141540, PubMed:21664385).
Mediates glucocorticoid-induced apoptosis (PubMed:23303127).
Promotes accurate chromosome segregation during mitosis (PubMed:25847991).
May act as a tumor suppressor (PubMed:25847991).
May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression (By similarity).
Isoform Beta
Acts as a dominant negative inhibitor of isoform Alpha (PubMed:7769088, PubMed:8621628, PubMed:20484466).
Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253).
Loses this transcription modulator function on its own (PubMed:20484466).
Has no hormone-binding activity (PubMed:8621628).
May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity).
Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253).
Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253).
Isoform Alpha-2
Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism (PubMed:20484466).
Isoform GR-P
Increases activity of isoform Alpha.
Isoform Alpha-B
More effective than isoform Alpha in transcriptional activation, but not repression activity.
Isoform 10
Has transcriptional activation activity.
Isoform Alpha-C1
Has transcriptional activation activity.
Isoform Alpha-C2
Has transcriptional activation activity.
Isoform Alpha-C3
Has highest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903).
Has transcriptional repression activity (PubMed:23303127).
Mediates glucocorticoid-induced apoptosis (PubMed:23303127, PubMed:23820903).
Isoform Alpha-D1
Has transcriptional activation activity.
Isoform Alpha-D2
Has transcriptional activation activity.
Isoform Alpha-D3
Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903).
Has transcriptional repression activity (PubMed:23303127).

Apoptotic processIEA:UniProtKB-KW
Cell cycleIEA:UniProtKB-KW
Cell divisionIEA:UniProtKB-KW
Cellular response to dexamethasone stimulusManual Assertion Based On ExperimentIMP:CAFA
Cellular response to glucocorticoid stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to steroid hormone stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to transforming growth factor beta stimulusManual Assertion Based On ExperimentIDA:CAFA
Chromatin organizationIEA:UniProtKB-KW
Chromosome segregationIEA:UniProtKB-KW
Intracellular steroid hormone receptor signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:NTNU_SB
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of miRNA transcriptionManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc

Isoform Alpha
Cytoplasm
Nucleus
Mitochondrion
Cytoplasm, cytoskeleton, spindle
Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
After ligand activation, translocates from the cytoplasm to the nucleus. In the presence of NR1D1 shows a time-dependent subcellular localization, localizing to the cytoplasm at ZT8 and to the nucleus at ZT20 (By similarity).
Lacks this diurnal pattern of localization in the absence of NR1D1, localizing to both nucleus and the cytoplasm at ZT8 and ZT20 (By similarity).
Isoform Beta
Nucleus
Cytoplasm
Expressed predominantly in the nucleus with some expression also detected in the cytoplasm.
Isoform Alpha-B
Nucleus
Cytoplasm
After ligand activation, translocates from the cytoplasm to the nucleus.

Glucocorticoid resistance, generalized (GCCR):
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.

Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity.2 Publications
Increased proteasome-mediated degradation in response to glucocorticoids (PubMed:11555652).
Isoform Alpha-B appears to be more susceptible to proteolytic degradation than isoform Alpha (PubMed:11435610).2 Publications
Phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid. The Ser-203, Ser-226 and Ser-404-phosphorylated forms are mainly cytoplasmic, and the Ser-211-phosphorylated form is nuclear (PubMed:12000743, PubMed:18838540).
Phosphorylation at Ser-211 increases transcriptional activity (PubMed:12000743, PubMed:18483179).
Phosphorylation at Ser-203, Ser-226 and Ser-404 decreases signaling capacity (PubMed:12000743, PubMed:18483179, PubMed:18838540).
Phosphorylation at Ser-404 may protect from glucocorticoid-induced apoptosis (PubMed:18838540).
Phosphorylation at Ser-203 and Ser-211 is not required in regulation of chromosome segregation (PubMed:25847991).
May be dephosphorylated by PPP5C, attenuates NR3C1 action (By similarity).
Sumoylation at Lys-277 and Lys-293 negatively regulates its transcriptional activity (PubMed:12144530).
Sumoylation at Lys-703 positively regulates its transcriptional activity in the presence of RWDD3 (By similarity).
Sumoylation at Lys-277 and Lys-293 is dispensable whereas sumoylation at Lys-703 is critical for the stimulatory effect of RWDD3 on its transcriptional activity (By similarity).
Heat shock increases sumoylation in a RWDD3-dependent manner (By similarity).
Ubiquitinated; restricts glucocorticoid-mediated transcriptional signaling.