Project description:Comparison of differences in gene expression in white and brown adipose tissues in the presence and absence of glucocorticoid receptor expression.
Project description:Comparison of differences in gene expression in white and brown adipose tissues in the presence and absence of glucocorticoid receptor expression.
Project description:Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) to regulate diverse biological functions from cell growth to apoptosis. Drugs that mimic their action are the most commonly prescribed therapeutic agents in the world and are currently used for the treatment of many diseases including asthma, autoimmune disorders, and some cancers. However, the mechanisms by which one hormone, via one receptor, modulates such diverse biological functions remain unclear. We hypothesized that epigenetic alteration to the GR may contribute to its signaling diversity, and here we demonstrate that Glycogen Synthase Kinase-3-beta phosphorylates GR on Serine 404 in a glucocorticoid-dependent manner. U-2 OS cells expressing a mutant GR that is incapable of Ser404 phosphorylation have enhanced global transcriptional responses, stronger NF-kappaB transrepression, and enhanced cell death in response to dexamethasone. Conversely, presence of Ser404 phosphorylation on the GR inhibits glucocorticoid-dependent NF-kappaB transrepression and cell death of these osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3-beta pathway with the GR resulting in altered glucocorticoid regulated signaling. Our results also provide a mechanism by which the phosphorylation status of Ser404 in GR can dictate how cells will ultimately respond to GCs. Keywords: Glucocorticoid Receptor; GSK-3-beta; NF-kappaB Transrepression; Phosphorylation
Project description:Glucocorticoid receptor (GR) has been recently identified as a candidate for acquired anti-androgen and chemotherapy resistance. In order to identify glucocorticoid receptor (GR) targets and studying stromal GR signaling gene expression profiling was performed in primary prostate cancer associated fibroblasts using different treatments.
Project description:Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. We screened the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discovered a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
Project description:Vascular inflammation is present in many cardiovascular diseases and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data has shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here we performed chromatin immunoprecipitation for the glucocorticoid receptor followed by next-gen sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a novel role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in up regulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Further we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway via a novel glucocorticoid response element gleaned from our genomic data. These results suggest a novel role for endothelial Wnt signaling modulation in states of vascular inflammation.
Project description:Vascular inflammation is present in many cardiovascular diseases and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data has shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here we performed chromatin immunoprecipitation for the glucocorticoid receptor followed by next-gen sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a novel role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in up regulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Further we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway via a novel glucocorticoid response element gleaned from our genomic data. These results suggest a novel role for endothelial Wnt signaling modulation in states of vascular inflammation.