Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA140563 | ENA |
REPOSITORIES: ENA
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Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone. U2OS cells, a human osteosarcoma cell line, were transfected with either WT GR or S134A GR and put under antibiotic selection to produce a stable mixed population of cells expressing comparable levels of GR. 10^6 cells were treated with 100nM Dexamethasone (DEX) or vehicle control for 6 hours. Three biological and one hybridization replicate are included for each sample.
2011-10-04 | E-GEOD-28912 | biostudies-arrayexpress
Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone.
2011-10-05 | GSE28912 | GEO
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
2008-11-24 | GSE11205 | GEO
Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies. We tested the hypothesis by treateing rats with the synthetic glucocorticoid dexamethasone and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR).
2010-07-30 | E-GEOD-22647 | biostudies-arrayexpress
Project description:Glucocorticoid Receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein (GRIP)1 of the p160 family has emerged as a unique GR corepressor in macrophages (MΦ), however, whether GRIP1 contributes to GR-activated transcription, and what dictates its context-specific coactivator vs. corepressor properties is unknown. We report that loss of GRIP1 in human and mouse MΦ attenuated GR-mediated induction of several anti-inflammatory targets, revealing a non-redundant function of GRIP1 in coactivation. Moreover, glucocorticoid treatment of quiescent MΦ globally directed GRIP1 toward GR-bound genomic sites dominated by classic palindromic GREs, suggesting its dedicated role as a GR coactivator. Further, GRIP1 N-terminal region was phosphorylated at a serine cluster by Cyclin-Dependent Kinase (CDK)9, which was recruited into GC-induced GR:GRIP1:CDK9 ternary complexes, producing distinct GRIP1 phospho-isoforms at different GREs even associated with the same gene. Functionally, phosphorylation potentiated GRIP1 coactivator properties by facilitating its recruitment and/or creating novel protein:protein interaction surfaces in a GRE-specific manner. Strikingly, GRIP1 function as a GR corepressor was phosphorylation-independent; consistently, no phospho-GRIP1 or CDK9 was detected at GR transrepression sites near pro-inflammatory genes. Thus, liganded GR in MΦ restricts actions of its own coregulator via CDK9-mediated phosphorylation to a subset of complexes driving anti-inflammatory gene transcription.
2017-09-29 | GSE99887 | GEO
Project description:ARGLU1 is a Transcriptional Coactivator and Splicing Regulator Important for Stress Hormone Signaling and Development Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neuronal cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neuronal cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neuronal cells with consequences for glucocorticoid signaling.
2019-02-15 | PXD012406 | Pride
Project description:ARGLU1 is a Transcriptional Coactivator and Splicing Regulator Important for Stress Hormone Signaling and Development Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neuronal cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neuronal cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neuronal cells with consequences for glucocorticoid signaling.
2019-02-15 | PXD012555 | Pride
Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies.
2010-06-30 | GSE22647 | GEO
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 a prostate cancer associated fibroblast cell model (PF179TCAF-shGR-1) using different treatments.
2021-06-01 | GSE150432 | GEO
Project description:Glucocorticoid receptor (GR) is a ligand dependent transcription factor that plays a central role in inflammation. Part of a complex cellular network, GR activity is further modulated via protein–protein interactions . The regulation of GR by 14-3-3 proteins has been previously reported, though with differing sites of phosphorylation identified and variable consequences assigned. Hence, we sought to examine this protein–protein interaction and, using phosphorylated GR peptides, biophysical studies and X-ray crystallography, we identified key residues within the ligand binding domain of GR, T524 and S617, whose phosphorylation results in recognition by 14-3-3. Investigation of the kinases responsible for phosphorylation of these sites assigned a key role for MINK1 and cell-based approaches confirmed the importance of these two GR phosphosites and MINK1 in GR–14-3-3 binding. Together our results provide a molecular-level insight into 14-3-3 regulation of GR and highlight both MINK1 and the GR–14-3-3 axis as potential targets for future therapeutic intervention.
2021-09-09 | PXD022364 | Pride