Glucocorticoid receptor
- Short name
- GR (Alternative name(s):Nuclear receptor subfamily 3 group C member 1)
- Function
- Receptor 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. Ref.37 Ref.41
- グルココルチコイドに対する受容体である。二通りのモード（1． glucocorticoid response elements (GRE)に結合する転写因子として核、ミトコンドリア両方のDNAに作用する。2．他の転写因子の調節因子として）で作用する。炎症反応に影響し、細胞の増殖、分化にかかわる。成長ホルモンによる刺激に基づくSTAT5依存の転写でコアクチベータ-として作用することで肝臓のGRは身体の成長の調節に重要な役割を持つ。クロマチンリモデリングに関与する。脂肪合成に対して脂肪分解と抗脂肪合成に関与する遺伝子発現調節を介して負の役割を持つ。
- Subunit structure
- Heteromultimeric 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 in a ligand-dependent fashion. Ref.17 Ref.18 Ref.19 Ref.22 Ref.29 Ref.31 Ref.32 Ref.33 Ref.37 Ref.42 Ref.43 Ref.61
- HSP90AA1, HSPA1A/HSPA1B, FKBP5 およびPPID, STIP1のようなimmunophilin、あるいはimmunophilinホモログのPPP5Cとヘテロ多量体を形成している。リガンドが結合すると、FKBP5が遊離しFKBP4と置き換わることにより複合体はダイニンに結合し核に運ばれそこで複合体は解離する。UNC45Aと直接相互作用する。ホモダイマーとなってDNAに結合する。NR3C2またはレチノイドX受容体とヘテロダイマーをつくりDNAに結合する。STAT5A および STAT5Bのホモまたはヘテロダイマーと結合する。NRIP1, POU2F1, POU2F2 and TRIM28と相互作用する。SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) や p160 coactivators such as NCOA2 and NCOA6などのいくつかのコアクチベータ-複合体と相互作用する。
- Subcellular location
- Cytoplasm. Mitochondrion. Nucleus. Note: Cytoplasmic in the absence of ligand, nuclear after ligand-binding. Ref.41 Ref.42
Isoform Beta: Nucleus. Note: Localized largely in the nucleus. Ref.41 Ref.42
- Tissue specificity
- Widely 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. Ref.21
Domain
N末端の調節ドメイン、DNA結合ドメイン、Ｃ末端のリガンド結合ドメイン
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. Ref.15
- Post-translational modification
- Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity. Ref.37 Ref.43
Increased proteasome-mediated degradation in response to glucocorticoids.
Phosphorylated 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. Ref.28
Sumoylated; this reduces transcription transactivation. Ref.27
Ubiquitinated; restricts glucocorticoid-mediated transcriptional signaling By similarity.
- Polymorphism
- Carriers 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.
- Involvement in disease
- Glucocorticoid resistance (GCRES) [MIM:138040]: Hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.
- Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.47 Ref.50 Ref.56 Ref.58 Ref.61
- Miscellaneous
- 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.
Can 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.
- Sequence similarities
- Belongs to the nuclear hormone receptor family. NR3 subfamily. / Contains 1 nuclear receptor DNA-binding domain.
Rho GTPase-activating protein 35
Alternative name(s):
- Glucocorticoid receptor DNA-binding factor 1
- Glucocorticoid receptor repression factor 1
- Short name=GRF-1
- Rho GAP p190A
- Short name=p190-A
Function
- Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'. May participate in the regulation of retinal development and degeneration. May transduce signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP). May also act as a tumor suppressor. Ref.5 Ref.6
Subunit structure
- Interacts with RASA1. Interacts with the general transcription factor GTF2I, the interaction sequesters GTF2I in the cytoplasm. Ref.18
Subcellular location
Cytoplasm By similarity. Nucleus By similarity.
Post-translational modification
Phosphorylation of Tyr-1105 by PTK6 promotes the association with RASA1, inactivating RHOA while activating RAS. Phosphorylation at Tyr-308 by PDGFRA inhibits binding to GTF2I.
Sequence similarities
Contains 4 FF domains.
Contains 1 Rho-GAP domain.
