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glucocorticoid receptor; GR; nuclear receptor subfamily 3 group C member 1 (NR3C1, GRL)

Function: - receptor for glucocorticoids - dual mode of action: a) transcription factor that binds to glucocorticoid response elements (GRE) b) modulator of other transcription factors - affects inflammatory responses, cellular proliferation & differentiation in target tissues - could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation - role of hepatic glucocorticoid in control of body growth (putative) - role in chromatin remodeling - role in transactivation - role in nuclear translocation (putative) - cytoplasmic anchoring &/or assembly associated with heat shock proteins hsp70 & hsp90 & immunophilin p59FKBP - heteromultimeric cytoplasmic complex with HSP90, HSP70, & FKBP5 or another immunophilin, or the immunophilin homolog PPP5C - directly interacts with UNC45A - upon ligand binding FKBP5 dissociates from the complex & FKBP4 takes its place, thereby linking the complex to dynein & mediating transport to the nucleus, where the complex dissociates (putative) - binds to DNA as a homodimer, & as a heterodimer with NR3C2 or the retinoid X receptor - binds STAT5A & STAT5B homodimers & heterodimers - interacts with NRIP1, POU2F1, POU2F2 & TRIM28 - interacts with NCOA1, NCOA3, SMARCA4, SMARCC1, SMARCD1, & SMARCE1 (putative) - interacts with several coactivator complexes, including SMARCA4 complex, CREBBP/EP300, TADA2L & p160 coactivators such as NCOA2 & NCOA6 - interaction with BAG1 inhibits transactivation - interacts with HEXIM1, PELP1 & TGFB1I1 - increased proteasome-mediated degradation in response to glucocorticoids - phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoid - Ser-203-phosphorylated form is mainly cytoplasmic, Ser-211-phosphorylated form is nuclear - transcriptional activity correlates with the amount of phosphorylation at Ser-211 - sumoylated; this reduces transcription transactivation - can up- or down-modulate aggregation & nuclear localization of expanded polyglutamine polypeptides derived from AR & HD through specific regulation of gene expression - aggregation & nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by this receptor, a well-characterized transcriptional regulator Structure: - composed of 3 domains: a) a modulating N-terminal domain b) a DNA-binding domain c) a C-terminal steroid-binding domain - belongs to the nuclear hormone receptor family, NR3 subfamily - contains 1 nuclear receptor DNA-binding domain Compartment: - cytoplasm, nucleus - cytoplasmic in the absence of ligand, nuclear after ligand-binding Alternative splicing: - alternative initiation - named isoforms=9 Expression: - widely expressed - in the heart, detected in left & right atria, left & right ventricles, aorta, apex, intraventricular septum, & atrioventricular node as well as whole adult & fetal heart - high 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 Pathology: - defects in NR3C1 are a cause of glucocorticoid resistance Polymorphism: - carriers of the 22-Glu-Lys-23 allele are relatively more resistant to the effects of glucocorticoids 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 - carriers of haplotype-3 have an more active proinflammatory system and carry an increased risk of cardiovascular disease 2.8 fold (homozygous) [3]

Interactions

molecular events

Related

glucocorticoid glucocorticoid receptor gene

Specific

glucocorticoid receptor-alpha glucocorticoid receptor-beta

General

human longevity protein nuclear hormone receptor NR3 subfamily steroid receptor

Properties

SIZE: MW = 86 kD entity length = 777 aa COMPARTMENT: cytoplasm cell nucleus MOTIF: MODULATING {1-420} MOTIF: Thr phosphorylation site {T8} Ser phosphorylation site {S45} Ser phosphorylation site {S113} Ser phosphorylation site {S134} Ser phosphorylation site {S141} Ser phosphorylation site {S203} Ser phosphorylation site {S211} Ser phosphorylation site {S226} Ser phosphorylation site {S234} Ser phosphorylation site {S267} threonine-rich region {399-418} MOTIF: threonine residue (SEVERAL) DNA-binding motif SITE: 421-486 MOTIF: Zn finger C4-type SITE: 421-441 EFFECTOR-BOUND: Zn+2 kvffkr NAME: kvffkr SITE: 442-447 FOR-BINDING-OF: calreticulin FORM: kvffkr Zn finger C4-type SITE: 457-481 EFFECTOR-BOUND: Zn+2 hinge region {487-527} binding site SITE: 528-777 FOR-BINDING-OF: steroid

Database Correlations

OMIM 138040 MORBIDMAP 138040 UniProt P04150 PFAM correlations Entrez Gene 2908 Kegg hsa:2908

References

  1. Alberts et al Molecular Biology of the Cell, 2nd ed. 1989, pg 704
  2. Barnes PJ & AdcockI Anti-inflammatory actions of steroids: molecular mechanisms. TIPS 14:436 1993 PMID: 7510080
  3. van den Akker et al, Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 2008, 168:33 PMID: 18195193
  4. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=NR3C1
  5. Wikipedia; Glucocorticoid receptor entry http://en.wikipedia.org/wiki/Glucocorticoid_receptor
  6. UniProt :accession P04150

Component-of

molecular complex