glucocorticoid receptor; GR; nuclear receptor subfamily 3 group C member 1 (NR3C1, GRL)
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Function
- receptor for glucocorticoids
- dual mode of action:
- transcription factor that binds to glucocorticoid response elements (GRE)
- 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 modulating N-terminal domain
- a DNA-binding domain
- a C-terminal steroid-binding domain
- belongs to the nuclear hormone receptor family, NR3 subfamily
- contains 1 nuclear receptor DNA-binding domain
Compartment
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]
More general terms
More specific terms
Additional terms
References
- ↑ Alberts et al Molecular Biology of the Cell, 2nd ed. 1989, pg 704
- ↑ Barnes PJ & AdcockI Anti-inflammatory actions of steroids: molecular mechanisms. TIPS 14:436 1993 PMID: https://www.ncbi.nlm.nih.gov/pubmed/7510080
- ↑ 3.0 3.1 van den Akker et al, Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 2008, 168:33 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18195193
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=NR3C1
- ↑ Wikipedia; Glucocorticoid receptor entry http://en.wikipedia.org/wiki/Glucocorticoid_receptor
- ↑ UniProt http://www.uniprot.org/uniprot/P04150.html