Endocrine Abstracts

The current model of glucocorticoid receptor (GR) action is well established, whereby GR remains inactive in the cytoplasm until bound by ligand, then rapidly translocates to the nucleus to regulate target genes. However, our recent observations challenge the simplicity of this model and suggest a greater range of GR action.We have identified a novel pathway in which the GR is recruited to the plasma membrane through binding to the lipid raft marker cave...

Glucocorticoids (Gc) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to treatment between individuals and over time. Generating a reversible model of Gc resistance in vitro that will mimic the cellular microenvironment in vivo is critical in (i) defining biomarkers that predict patient steroid responsiveness; (ii) provide a model to screen new GR modulators capable of potentiating GR ...

Glucocorticoids (GCs) are used extensively in the treatment of inflammatory disease. Unfortunately, as GC act on virtually every organ system they also carry a broad range of serious side-effects which limits their clinical use.The structure of the bound GC strongly impacts the final conformation of the glucocorticoid receptor (GR) and thereby dictates downstream events. Designing drugs with different GR binding properties therefore offers a plausible ro...

Although glucocorticoids (Gc) are used to treat a range of pathologies, an individuals response to therapy varies considerably. There is a distinct correlation between certain cell types and steroid sensitivity. Aberrant glucocorticoid receptor (GR) function is well-characterised in lymphoid malignant cells but not small cell lung cancer (SCLC) (DMS79) or osteosarcoma (U2OS) cell lines, which are both Gc resistant.Previously we have shown reduced GR cont...

Many glucocorticoid (Gc) actions are of rapid onset, and therefore require acute regulation of intracellular signalling cascades. We have previously identified rapid Gc-dependent activation of the caveolae specific integral membrane protein caveolin, and the cytosolic kinase PKB in the lung epithelial cells, A549.Immunofluorescence studies demonstrate the appearance of activated glucocorticoid receptor (P-ser211-GR) localised to focal points around the c...

Glucocorticoids (GCs) are steroid hormones used to treat inflammatory diseases such as rheumatoid arthritis, but their clinical efficacy is hampered by development of side effects such as impaired wound healing. GCs bind the glucocorticoid receptor (GR) to mediate cellular effects. The inactive GR is held in multi-protein complex in the cytoplasm and upon ligand binding undergoes a conformational change, interacts with cytoplasmic enzymes to mediate non-genomic effects (within...

Glucocorticoids act through the glucocorticoid receptor (GR) to regulate cell function. GR gamma (GRγ) is a constitutive exon3/4 splice variant, contributing 4–8% of the total GR transcripts and is highly conserved through mammalian evolution, but its biological function remains unknown. Using microarray analysis we identified the transcriptome response for GRγ in stable HEK-Flp cells. This revealed that although GRγ effectively modulated gene expression in...

Glucocorticoids (Gcs) act via the intracellular glucocorticoid receptor (GR) to regulate cellular homeostasis. GR is a ligand-activated transcription factor which mediates effects within the nucleus or cytoplasm to regulate genomic or non-genomic events. Localisation of the GR to a specific cellular compartment is therefore an important determinant of the cellular response to Gcs.Live cell imaging of GR trafficking in cells transfected with fluorophore-t...

Synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligands are used clinically to improve insulin sensitivity. Although designed as specific ligands for PPARγ, there is evidence for some ‘off target’ effects being mediated by a non-classical, non-PPARγ mechanism. Recent evidence further suggests that some of these effects may be glucocorticoid receptor (GR)-dependent.To analyse activation of GR following exposure ...

Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to regulate immunity, energy metabolism, and tissue repair. The inactive GR is held in the cytoplasm in a multi-protein complex, which upon ligand binding undergoes a conformational change. Activated GR translocates to the nucleus to regulate gene expression (over hours), but some effects occur more rapidly. Gc inhibit cell migration through an uncertain mechanism. We now show a very rapid effect, and surprising...