Endocrine Abstracts

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...

Variation in glucocorticoid (Gc) sensitivity underlies metabolic disease, and affects therapeutic response in inflammation. Using an in-vitro screening approach we identify two new mechanisms capable of regulating Gc sensitivity.The first involves interferon induced factor 16 (IFI16). IFI16 potentiated both transactivation, and Gc repression of NFκB. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand dependent repression of GR expr...

Introduction: Glucocorticoid replacement therapy uses twice or thrice daily regimens of hydrocortisone (HC) with variable distribution of the dose over the day. Deconvolution analysis determines the mass of hormone that needs to be secreted to attain a particular serum concentration. We have used this methodology to determine the amount and distribution of cortisol over a 24 h period.Methods: Seventy-nine adults (41M) aged 60–74 years and 30 childre...

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) are the most potent anti-inflammatory agents known and are used extensively in the treatment of inflammatory disease, however an individuals response to therapy varies greatly. Resistance to GC is often attributed to mutations within the glucocorticoid receptor (GR) through which GC elicit their effects. Here, we present a kindred with GR haploinsufficiency yet no clinical phenotype. PCR and GR sequence profiling of genomic DNA isolated from patient blood...

Glucocorticoids (Gcs) act via the intracellular glucocorticoid receptor (GR) to regulate cellular homeostasis. GR is a ligand-activated transcription factor that mediates effects within the nucleus or cytoplasm to regulate genomic and 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 using fluorophore-tagged GR shows drama...

The actions of glucocorticoids (Gc) are mediated by the glucocorticoid receptor (GR). Several isoforms of the GR exist. Whilst GR alpha is the most abundant isoform, constitutive alternative splicing at the exon 3/exon 4 boundary results in an additional arginine within the DNA binding domain to produce the gamma isoform. Although GR gamma comprises 4–8% of total GR transcripts and is highly conserved through mammalian evolution, its biological function remains unknown.</...

Glucocorticoids (Gcs) act via the intracellular glucocorticoid receptor (GR) to regulate cellular homeostasis. Previous studies have demonstrated altered Gc sensitivity during mitosis. This reduced sensitivity can be explained only in part through the selective export of GR in mitotic cell populations. In this study ligand-independent, cell cycle-dependent effects on GR have been explored.Mitotic cells show a marked increase in ligand-independent ser211 ...