Development Glucocorticoid receptor signaling
Glucocorticoid receptor signaling Glucocorticoids contribute to the maintenance of basal and stress-relatedhomeostasis in all higher organisms. Glucocorticoids and their syntheticderivatives work through the nuclear Receptor subfamily 3 group C member 1(glucocorticoid receptor) ( GCR ). GCR is a member of the nuclear hormonereceptor superfamily of ligand-activated transcription factors. GCR mediatestransactivation of target genes by binding glucocorticoid response elements in theirpromoter region. The GCR gene encodes two splicing variants, GCR-alpha andGCR-beta , . The GCR must be bound to the protein chaperone Heat shock protein 90kDa (HSP90 ) in order to acquire the high affinity steroid binding conformation . Unligated cytoplasmic GCR exists as a heteromeric complex that containsa dimer of HSP90, an immunophilin protein of the FK506 binding protein family(for example, FK506 binding protein 4, 59kDa ( FKBP4 )), and Prostaglandin Esynthase 3 ( p23 co-chaperone ). Other immunophilins or heat shock proteins (forexample, HSP70 ) that are found associated with unliganded steroid receptors arelikely to be involved in the maturation of the receptor to its hormone-bindingconformation. Also, probably HSP90 and HSP70 play role in regulation ofnuclear trafficking of GCR . GCR is covalently modified by SMT3 suppressor of mif two 3 homolog 1 (SUMO-1 ). Sumoylation influences GCR function. SUMO-1 overexpressioninduces GCR degradation. Also SUMO-1 stimulates the transactivationcapacity of GCR , . GCR sumoylation mayalso regulate negatively transcriptional activity of Jun oncogene ( c-Jun ) . Ubiquitin-conjugating enzyme E2I ( E2I ) binds SUMO and caninteract with SUMO noncovalently. The noncovalent interaction promotes theformation of short SUMO chains on targets and so promotes its activity . Also E2I binds to GCR. E2I displays no intrinsictransactivation activity. However, it modifies both the absolute amount of induced geneproduct, and the fold induction by GCR. With high concentrations of GCR,added E2I also reduces the EC50 of agonists and increases the partial agonistactivity of antagonists  GCR interacts with Nuclear receptor coactivator 1 and 2 ( NCOA1(SRC1) and ( NCOA2 (GRIP1/TIF2) ), that acts as corepressors . GCR and corepressor NCOA2 inhibit Activator protein 1 (AP-1 ) and so induce AP-1 -mediated gene expression, for example Matrixmetallopeptidase 13 ( MMP-13 ). The repression is not dependent on AP-1subunits composition, for example Jun oncogene/v-fos FBJ murine osteosarcoma viraloncogene homolog ( c-Jun/c-Fos ) , . GCRinhibits Transforming growth factor beta ( TGF-beta ) signaling by directlytargeting the transcriptional activation function of SMAD family member 3 ( SMAD3) ,  in conjunction with NCOA1 and NCOA2. Thus, for example, GCR can prevent TGF -dependentSMAD3 -mediated Serpin peptidase inhibitor clade E member 1 ( PAI1 )expression . Also GCR-alpha inhibits gene expression via supression of Nuclear factor kappaB( NF-kB ) activity . GCR-alpha binding to NF-kBleads to inactivation of both proteins . GCR-alpha also can inducetranscription of Nuclear factor of kappa light polypeptide gene enhancer in B-cellsinhibitor, alpha ( NFKBIA ), a NF-kB inhibitor , , . GCR can interact productively with the POU class 2 homeobox 1 and 2 (Oct-1 and Oct-2 ) proteins to recruit them to DNA and this contributes toactivation of transcription by Oct from glucocorticoid-responsive promoters , . Activated GCR forms a complex with Signal transducer and activator oftranscription 5 ( STAT5 ) and enhances STAT5 -mediated transcriptionalinduction . GCR increases DNA-binding activity of CCAAT/enhancer bindingprotein beta ( C/EBPbeta ) . GCR interacts with CREB binding protein ( CBP ) and E1A binding proteinp300 ( p300 ) and competes with their transcription factors ,. GCR-beta has been shown to inhibit the effects of hormone-activatedGCR-alpha on a glucocorticoid-responsive reporter gene in aconcentration-dependent manner due to competition for glucocorticoid response elementtarget sites .