NR3C1

GeneName

NR3C1

Summary

NR3C1, commonly referred to as the glucocorticoid receptor (GRL), is a 86 kDa nuclear receptor that functions primarily as a transcription factor regulating gene expression in response to glucocorticoids. It is expressed in various tissues, including the brain, liver, and immune cells, and is involved in numerous biological processes such as apoptosis, cell division, and the cellular response to steroid hormones. NR3C1 is localised in multiple cellular compartments including the nucleus, cytoplasm, and mitochondria, and plays a role in chromatin organisation and transcription regulation by binding to specific DNA sequences and interacting with other proteins. Its activity is modulated by various stimuli, including dexamethasone and cortisol, highlighting its significance in stress response and metabolic processes.

Importance

NR3C1 is relevant to: - The regulation of immune responses and inflammation, impacting conditions such as autoimmune diseases and allergies. - Metabolic disorders, including diabetes and obesity, due to its role in gluconeogenesis and glucocorticoid metabolism. - Neuroinflammation and neurodegenerative diseases, as it influences neuronal apoptosis and microglia differentiation. - Developmental processes, such as adrenal gland and mammary gland development, reflecting its importance in endocrine function.

Top Products

For researchers investigating NR3C1, we recommend two excellent primary antibodies. The first is the well-cited Anti-Glucocorticoid Receptor antibody [BuGR2] (ab2768), a monoclonal antibody that has garnered 46 citations, highlighting its reliability in Western blotting (WB), immunocytochemistry (ICC), and flow cytometry (FC). Additionally, we offer the recombinant antibody, Anti-Glucocorticoid Receptor antibody [EPR19621] (ab183127), which has been validated in knockout models and is suitable for a broader range of applications, including WB, immunohistochemistry (IHC), ICC, and FC. With 20 citations, this recombinant antibody is an excellent choice for researchers seeking consistent performance across experiments.

Abcam Product Citation Summary

The data indicates that NR3C1 antibodies from Abcam have been employed in various species, including Ovis aries, Rattus norvegicus, Cavia porcellus, and humans, primarily for Western blotting and immunocytochemistry applications. The studies focus on different biological contexts such as myocardium, glucocorticoid receptor expression, signaling, and germ cell tumors.

Abcam Product Citation Table

Domain

Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain (PubMed:3841189). The ligand-binding domain is required for correct chromosome segregation during mitosis although ligand binding is not required (PubMed:25847991).

Function

Receptor for glucocorticoids (GC) (PubMed:27120390, PubMed:37478846). 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 (PubMed:28139699). 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:11435610, PubMed:15769988, PubMed:15866175, PubMed:17635946, PubMed:19141540, PubMed:19248771, PubMed:20484466, PubMed:21664385, PubMed:23820903). 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:20484466, PubMed:7769088, PubMed:8621628). 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).

Involvement in disease

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity.

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).

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).

Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound NR3C1 when it is not associated with coactivators (NCOAs) (PubMed:37478846). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation (PubMed:37478846).

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).

Sequence Similarities

Belongs to the nuclear hormone receptor family. NR3 subfamily.

Tissue Specificity

Widely expressed including bone, stomach, lung, liver, colon, breast, ovary, pancreas and kidney (PubMed:25847991). 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 (PubMed:10902803).

Isoform Beta

Widely expressed including brain, bone marrow, thymus, spleen, liver, kidney, pancreas, lung, fat, skeletal muscle, heart, placenta and blood leukocytes.

Isoform Alpha-2

Widely expressed.

Cellular localization

• Isoform Alpha
• Cytoplasm
• Nucleus
• Mitochondrion
• Cytoplasm
• Cytoskeleton
• Spindle
• Cytoplasm
• Cytoskeleton
• Microtubule organizing center
• Centrosome
• Chromosome
• Nucleus
• Nucleoplasm
• After ligand activation, translocates from the cytoplasm to the nucleus (PubMed:30698747). The hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment (By similarity). 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). Upon dexamethasone binding associates with the glucocorticoid response elements of target genes (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.

Alternative names

GRL, NR3C1, Glucocorticoid receptor, GR, Nuclear receptor subfamily 3 group C member 1

Database links

swissprot:P04150 omim:138040 entrezGene:2908

Other research areas

• Epigenetics
• Neuroscience