Similar Datasets
Project description:The goal of these studies is to identify genes that are regulated by glucocorticoids in human peripheral blood mononuclear cells in vitro.
2018-02-03 | GSE110098 | GEO
Project description:The goal of these studies is to identify genes that are regulated by glucocorticoids in human peripheral blood mononuclear cells in vitro.
2018-02-06 | GSE110156 | GEO
Project description:Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts in solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the altered transcriptional activity of GR following treatment with agonists, antagonists or lead selective GR agonists and modulators (SEGRAMs), we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that the GR antagonist RU486 and the SEGRAM Dagrocorat both reduced GR interaction with CREB-binding protein (CBP)/p300 and the mediator complex compared to the full agonist Dexamethasone. Our data offer new insights into the role differential coregulator protein recruitment in shaping specific GR-mediated transcriptional responses.
2024-05-24 | PXD042014 | Pride
Project description:The project is directed to the development of selective glucocorticoid receptor agonists for anticancer therapy. Glucocorticoids (GC) are widely used in treatment of many types of cancer due to its ability to induce apoptosis in malignant cells (in blood cancer therapy) and to prevent nausea and emesis (in the chemotherapy of solid tumors). However, severe dose-limiting side effects occur, including osteoporosis, muscle wasting, diabetes and other metabolic complications. Both beneficial and harmful effects of glucocorticoids are due to selective activation or repression of particular genes by glucocorticoid receptor (GR). GR regulates gene expression via transactivation that requires GR homodimer binding to gene promoters and transrepression mediated via negative interaction between GR and other transcription factors as well as binding with negative glucocorticoid response elements (nGRE) in genes. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. Novel selective GR agonist Compound A (CpdA) prevents GR dimerization and transactivation, specifically activates GR transrepression, and has fewer side effects compared to glucocorticoids. Here we compare the gene expression profiles in lymphoma cells treated with glucocorticoid Dexamethasone (Dex) or CpdA
2015-07-21 | GSE71102 | GEO
Project description:The project is directed to the development of selective glucocorticoid receptor agonists for anticancer therapy. Glucocorticoids (GC) are widely used in treatment of many types of cancer due to its ability to induce apoptosis in malignant cells (in blood cancer therapy) and to prevent nausea and emesis (in the chemotherapy of solid tumors). However, severe dose-limiting side effects occur, including osteoporosis, muscle wasting, diabetes and other metabolic complications. Both beneficial and harmful effects of glucocorticoids are due to selective activation or repression of particular genes by glucocorticoid receptor (GR). GR regulates gene expression via transactivation that requires GR homodimer binding to gene promoters and transrepression mediated via negative interaction between GR and other transcription factors as well as binding with negative glucocorticoid response elements (nGRE) in genes. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. Novel selective GR agonist Compound A (CpdA) prevents GR dimerization and transactivation, specifically activates GR transrepression, and has fewer side effects compared to glucocorticoids. Here we compare the gene expression profiles in prostate cancer cells treated with glucocorticoid Dexamethasone (Dex) or CpdA
2015-07-21 | GSE71099 | GEO
Project description:Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-? (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.
2020-07-20 | GSE115363 | GEO
Project description:The goal of this project is to investigate the role of glucocorticoids and their receptor, glucocorticoid receptor (GR) , in intestinal stress response and tissue homeostasis.We generated a mouse model with specific deletion of GR in intestinal epithelium (GR iKO mice) and examined colonic transcriptomes of adrenalectomized (ADX) Flox control and GR iKO mice in response to dexamethasone (DEX) treatment by microarray analysis.
2021-11-15 | GSE146086 | GEO
Project description:Mammalian lung development during the saccular and alveolar stages is dependent upon antagonistic molecular signalling by endogenous retinoic acid (RA) and glucocorticoids (GCs) which regulate gene expression via the retinoic acid receptor (RAR) family and the glucocorticoid receptor (GR), respectively. The genomic mechanism of this antagonism was investigated with in vitro distal lung explant cultures from E18.5 GR-null (GR-/-) mice treated with all-trans-RA (atRA) for 2h . Whole mouse genome microarray analysis from lung explant tissue identified a small number of gene targets which were not only significantly induced by atRA in the wildtype lung, but also significantly stimulated to levels greater than atRA-treated wildtype lungs in GR-/- lungs.
2014-01-12 | E-MEXP-3833 | biostudies-arrayexpress
Project description:Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs), able to separate anti-inflammatory effects via gene suppression from metabolic effects via gene activation, have been unsuccessful so far. In this study, we characterized a set of functionally diverse GR ligands in A549 cells, first using a panel of luciferase-based reporter gene assays evaluating GR-driven gene activation and gene suppression. We expanded this minimal assay set with novel luciferase-based read-outs monitoring GR protein levels, GR dimerization and GR Serine 211 (Ser211) phosphorylation status and compared their outcomes with compound effects on the mRNA levels of known GR target genes in A549 cells and primary hepatocytes. We found that luciferase reporters evaluating GR-driven gene activation and gene repression were not always reliable predictors for effects on endogenous target genes. Remarkably, our novel assay monitoring GR Ser211 phosphorylation levels proved to be the most reliable predictor for compound effects on almost all tested endogenous GR targets, both driven by gene activation and repression. The integration of this novel assay in existing screening platforms may therefore increase chances to find novel GR ligands with an improved therapeutic benefit.
2022-04-10 | PXD031319 | Pride
Project description:Glucocorticoids are primary stress hormones that regulate many physiological processes, and synthetic derivatives of these molecules and are widely used in the clinic. The cellular response to glucocorticoids is remarkably diverse; however, the molecular factors that govern tissue specificity are poorly understood. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). To discover new proteins that interact with GR and modulate its function, we performed a yeast 2 hybrid assay using as bait the hinge region of GR. The MyoD family inhibitor domain-containing (MDFIC) protein was identified as a binding partner for GR. To investigate the function of the GR-MDFIC interaction, we performed a genome-wide microarray in intact and MDFIC deficient A549 cells that were treated with the synthetic glucocorticoid Dexamethasone (Dex). A large cohort of genes was differentially regulated by GR depending on the presence or absence of MDFIC. These findings identify a new binding partner for cytoplasmic GR that modulates the receptor transcriptome and contributes to the tissue specific actions of glucocorticoids.
2017-04-07 | GSE86115 | GEO