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 , .
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 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 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 , .
GCR sumoylation may also regulate negatively transcriptional
activity of Jun oncogene (c-Jun) .
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 . 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 
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 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) , .
GCR inhibits Transforming growth factor beta
(TGF-beta) signaling by directly targeting the
transcriptional activation function of SMAD family member 3
(SMAD3) ,  in conjunction
with NCOA1 and NCOA2 . Thus, for example, GCR can prevent
Serpin peptidase inhibitor clade E member 1 (PAI1)
Also GCR-alpha inhibits gene expression via supression of
Nuclear factor kappaB (NF-kB) activity .
GCR-alpha binding to NF-kB
leads to inactivation of both proteins .
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
, , .
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 , .
Activated GCR forms a complex with Signal transducer and
activator of transcription 5 (STAT5) and enhances
STAT5-mediated transcriptional induction .
GCR increases DNA-binding activity of CCAAT/enhancer binding protein beta
GCR interacts with CREB binding protein
(CBP) and E1A binding protein p300
(p300) and competes with their transcription factors , .
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 .
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