Pathway Map Details

Development_Glucocorticoid receptor signaling

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p23 co-chaperone, NCOA2 (GRIP1/TIF2), GCR-beta, GCR-alpha, GCR-alpha, c-Jun/c-Fos, TGF-beta receptor type I, HSP90, NF-kB, Oct-1, FKBP4, SMAD3, C/EBPbeta, HSP70, PAI1, E2I, p300, NCOA1 (SRC1), MMP-13, SUMO-1, NFKBIA, CBP, glucocorticoids, Oct-2, STAT5


Glucocorticoid receptor signaling

Glucocorticoids contribute to the maintenance of basal and stress-related homeostasis in all higher organisms. Glucocorticoids and their synthetic derivatives work through the nuclear Receptor subfamily 3 group C member 1 (glucocorticoid receptor) ( GCR ). GCR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. GCR mediates transactivation of target genes by binding glucocorticoid response elements in their promoter region. The GCR gene encodes two splicing variants, GCR-alpha and GCR-beta [1], [2].

The GCR must be bound to the protein chaperone Heat shock protein 90kDa ( HSP90 ) in order to acquire the high affinity steroid binding conformation [3]. Unligated cytoplasmic GCR exists as a heteromeric complex that contains a dimer of HSP90, an immunophilin protein of the FK506 binding protein family (for example, FK506 binding protein 4, 59kDa ( FKBP4 )), and Prostaglandin E synthase 3 ( p23 co-chaperone ). Other immunophilins or heat shock proteins (for example, HSP70 ) that are found associated with unliganded steroid receptors are likely to be involved in the maturation of the receptor to its hormone-binding conformation. Also, probably HSP90 and HSP70 play role in regulation of nuclear trafficking of GCR [4].

GCR is covalently modified by SMT3 suppressor of mif two 3 homolog 1 ( SUMO-1 ). Sumoylation influences GCR function. SUMO-1 overexpression induces GCR degradation. Also SUMO-1 stimulates the transactivation capacity of GCR [5], [6]. GCR sumoylation may also regulate negatively transcriptional activity of Jun oncogene ( c-Jun ) [5]. Ubiquitin-conjugating enzyme E2I ( E2I ) binds SUMO and can interact with SUMO noncovalently. The noncovalent interaction promotes the formation of short SUMO chains on targets and so promotes its activity [7]. Also E2I binds to GCR. E2I displays no intrinsic transactivation activity. However, it modifies both the absolute amount of induced gene product, and the fold induction by GCR. With high concentrations of GCR, added E2I also reduces the EC50 of agonists and increases the partial agonist activity of antagonists [8]

GCR interacts with Nuclear receptor coactivator 1 and 2 ( NCOA1 (SRC1) and ( NCOA2 (GRIP1/TIF2) ), that acts as corepressors [9]. GCR and corepressor NCOA2 inhibit Activator protein 1 ( AP-1 ) and so induce AP-1 -mediated gene expression, for example Matrix metallopeptidase 13 ( MMP-13 ). The repression is not dependent on AP-1 subunits composition, for example Jun oncogene/v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Jun/c-Fos ) [10], [11]. GCR inhibits Transforming growth factor beta ( TGF-beta ) signaling by directly targeting the transcriptional activation function of SMAD family member 3 ( SMAD3 ) [12], [11] in conjunction with NCOA1 and NCOA2 [9]. Thus, for example, GCR can prevent TGF -dependent SMAD3 -mediated Serpin peptidase inhibitor clade E member 1 ( PAI1 ) expression [12].

Also GCR-alpha inhibits gene expression via supression of Nuclear factor kappaB ( NF-kB ) activity [11]. GCR-alpha binding to NF-kB leads to inactivation of both proteins [13]. GCR-alpha also can induce transcription of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha ( NFKBIA ), a NF-kB inhibitor [14], [15], [16].

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 to activation of transcription by Oct from glucocorticoid-responsive promoters [17], [18].

Activated GCR forms a complex with Signal transducer and activator of transcription 5 ( STAT5 ) and enhances STAT5 -mediated transcriptional induction [19]. GCR increases DNA-binding activity of CCAAT/enhancer binding protein beta ( C/EBPbeta ) [20].

GCR interacts with CREB binding protein ( CBP ) and E1A binding protein p300 ( p300 ) and competes with their transcription factors [21], [15].

GCR-beta has been shown to inhibit the effects of hormone-activated GCR-alpha on a glucocorticoid-responsive reporter gene in a concentration-dependent manner due to competition for glucocorticoid response element target sites [22].


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