The physiological and pharmacological actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes by direct binding to DNA response elements and/or by physically associating with other transcription factors.
Glucocorticoids are steroid hormones that exert their biological functions through the intracellular glucocorticoid receptor (GR). GR is a transcriptional regulator that, upon binding to cognate ligands, occupies specific genomic glucocorticoid response elements (GREs) and modulates the transcription of nearby genes. It is expressed in virtually every cell in the human body. Its ligand, cortisol, is a circulating hormone that varies in level throughout the day and in response to various external stimuli. Cortisol stimulation elicits different phenotypic responses in different cell types, including: gluconeogenesis in hepatocytes, suppression of bone formation by osteoblasts, differentiation or apoptosis in immature lymphocytes, and anti-inflammatory programs in immune system cells. It also induces apoptosis or proliferation in various cancer cell lines.
Glucocorticoid Receptor Signal Pathway
Inactive glucocorticoid receptor (GR) resides in the cytoplasm of intact cells, as a complex associated with several proteins including heat shock proteins (HSPs). Heat shock protein 90 (Hsp90) plays a significant role in conferring ligand-inducibility to GR. Just like other members of the steroid/thyroid super-family of receptors, GR is a ligand dependent transcription factor. Binding of glucocorticoid to GR causes structural changes in the complex that result in transformation of the receptor. The new conformation allows exposure of the nuclear translocation signal (NL1) and DNA-binding domain of GR. This leads to its rapid translocation to the nucleus. In the nucleus, GR undergoes dimerization and the dimer tightly binds to its cognate responsive elements (GRE) in the promoter region of the target genes. Various coactivator proteins, such as Glucocorticoid Receptor Interacting Protein (GRIP), Steroid Receptor Coactivator 1 (SRC1), interact with the active dimer and enhance the assembly of other transcriptional machinery. This orchestrates the regulation of gene expression mediated by GR. Apart from GRE-mediated gene expression, GR also has the ability to regulate the transactivity of various transcription factors, such as NFkB, API, STAT3, by a mechanism involving direct protein-protein interaction. GR signaling pathway is complex and plays a vital cytoprotective role in cells subjected to environmental as well as physiological stress. Due to a versatile regulatory mechanism, GR influences multiple aspects of cell-signaling processes and physiology. Significant scientific evidence has established the cross talk between GR signaling and HS signaling pathway.
Based on conventional views, physiological ligands such as cortisol and corticosterone, and synthetic compounds such as dexamethasone and prednisolone, are agonists that promote the biological functions of GR, whereas ligands such as RU486 are antagonists that bind to GR but inhibit its functions. It is now apparent, however, that ligand activities are strongly context dependent. For example, selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are agonist-like or antagonist-like in different tissues, and modulate distinct subsets of ER target genes in a given cell type; selective ligands for FXR have also been reported. Accordingly, the definitions of agonist and antagonist are relative to particular phenotypes or specific subsets of target genes, and therefore it is likely that any ligand could act as either agonist or antagonist depending on the context.
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