Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-13887
PROVIDER: PRJNA110359 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CD3-positive T cells were negatively isolated from 10 SLE patients and 9 healthy controls without SLE. All of the SLE samples and control samples were compared with one another to identify baseline differences in expression due to the disease. Next, T cell preparations from 4 of the control subjects were stimulated with either Nitric Oxide (NOC-18) 600 uM for 24hr or stimulated through CD3/CD28 for 24hr to determine which genes were responsive to these signaling mechanisms. Here, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in SLE T cells. Activation of mTOR was inducible by NO, a key trigger of MHP which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in SLE T cells and, in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 over-expression was also inversely correlated with diminished TCRζ protein levels. Combined with follow up studies, these results suggest that activation of mTOR causes the loss of TCRζ in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation. Experiment Overall Design: 10 replicate T cell samples from SLE (Lupus) patients Experiment Overall Design: 9 replicate T cell samples from healthy control (BC) subjects Experiment Overall Design: 4 replicate Nitric Oxide (NOC-18) stimulated T cell samples from 4 of the control subjects Experiment Overall Design: 4 replicate CD3/CD28 stimulated T cell samples from 4 of the control subjects
2009-02-28 | E-GEOD-13887 | biostudies-arrayexpress
Project description:CD3-positive T cells were negatively isolated from 10 SLE patients and 9 healthy controls without SLE. All of the SLE samples and control samples were compared with one another to identify baseline differences in expression due to the disease. Next, T cell preparations from 4 of the control subjects were stimulated with either Nitric Oxide (NOC-18) 600 uM for 24hr or stimulated through CD3/CD28 for 24hr to determine which genes were responsive to these signaling mechanisms. Here, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in SLE T cells. Activation of mTOR was inducible by NO, a key trigger of MHP which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in SLE T cells and, in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 over-expression was also inversely correlated with diminished TCRζ protein levels. Combined with follow up studies, these results suggest that activation of mTOR causes the loss of TCRζ in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation.
2009-02-20 | GSE13887 | GEO
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism. conditional activation of pkb and pi3k were followed in a timeseries. Each timepoint consists of 4 independent replicates, labeled with either cy3 or cy5 and put on array against time0.
2012-07-21 | E-GEOD-35701 | biostudies-arrayexpress
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism. conditional activation of foxo3 and foxo4 were followed in a timeseries. Each timepoint consists of 4 independent replicates, labeled with either cy3 or cy5 and put on array against time0 as reference.
2012-07-21 | E-GEOD-35703 | biostudies-arrayexpress
Project description:The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism-independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of Gal8 with mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery. Thus, a novel galectin-based signal-transduction apparatus, termed here GALTOR, controls mTOR in response to lysosomal damage.
2017-12-07 | MSV000081788 | MassIVE
Project description:MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. Some tumors bypass this regulatory circuit via genetic alterations that drive MiT/TFE expression and activity; however, the mechanisms by which cells with intact or constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we find that epidermal Tsc1 deletion results in a wavy hair phenotype due to increased EGFR degradation. Unexpectedly, constitutive mTORC1 activation increases lysosomal content via up-regulated expression and activity of MiT/TFEs, while genetic or prolonged pharmacologic mTORC1 inactivation has the reverse effect. This paradoxical up-regulation of lysosomal biogenesis by mTORC1 is mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE proteasomal degradation. These data suggest that oncogenic feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.
2020-04-14 | GSE124754 | GEO
Project description:Emerging evidences suggest that both function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how lysosomes function is linked to their position and thereby control metastatic progression remains elusive. Here, we analyzed lysosome subcellular distribution in micropatterned patient-derived melanoma cells and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote invadopodia-based matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in a zebrafish metastasis model significantly reduces invasive outgrowth. Our study provides a mechanistic demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis.
2023-07-31 | E-MTAB-13165 | biostudies-arrayexpress
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism.
2012-07-22 | GSE35703 | GEO
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism.
2012-07-22 | GSE35701 | GEO
Project description:Anti-malaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis, without clear mechanism of action. Here we report that chloroquine potently inhibits the expression of proinflammatory cytokines through transrepression of glucocorticoid receptor (GR). Instead of direct binding to GR, chloroquine synergistically activates glucocorticoid signaling via inhibition of lysosomal functions. In mouse collagen induced arthritis model, chloroquine synergizes the therapeutic effects of glucocorticoid. Lysosomal inhibition by bafilomycin A1, an inhibitor of V-type ATPase, or by knockdown of transcription factor EB (TFEB), a master activator of lysosomal biogenesis, mimics the effects of chloroquine. These results reveal an unexpected regulation of glucocorticoid signaling by lysosomes and provide a mechanistic basis for treating inflammation and autoimmune diseases by combination of glucocorticoids and lysosomal inhibitors. Macrophage THP-1 cells treated with LPS, chloroquine and dexamethasone.
2012-01-18 | E-GEOD-24579 | biostudies-arrayexpress