A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147950 | GEO | 2021/02/08
REPOSITORIES: GEO
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Project description:A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse]
| PRJNA622593 | ENA
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-bM-^@M-^\low/low/high/lowM-bM-^@M-^] or M-bM-^@M-^\LLHLM-bM-^@M-^]. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb Mouse embryo fibroblasts (MEFs) wild type or deficient in Tsc2 expressing a Tfeb shRNA or scrambled shRNA vector were treated with 25 nM rapamycin or vehicle (methanol) for 24 h under low serum conditions (0.1% FBS)
2011-08-02 | E-GEOD-28021 | biostudies-arrayexpress
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-^Slow/low/high/lowM-^T or M-^SLLHLM-^T, which allowed the identification of genes regulated by mTORC1 by performing the appropriate comparisons
2011-08-02 | E-GEOD-27982 | biostudies-arrayexpress
Project description:To screen miRNAs specifically regulated by mTORC1 or mTORC2, a global miRNA expression profile in MCF-7 cells treated with rapamycin or PP242 (mTORC1/2 kinase inhibitor) was developed using microarray. control, rapamycin or PP242 treated human MCF-7 cells were harvested 48h post-treatment and subjected to total RNA extraction.
2014-09-11 | E-GEOD-61289 | biostudies-arrayexpress
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a “low/low/high/low” or “LLHL”, which allowed the identification of genes regulated by mTORC1 by performing the appropriate comparisons
2011-08-03 | GSE27982 | GEO
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a “low/low/high/low” or “LLHL”. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb
2011-08-03 | GSE28021 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
2022-11-01 | GSE216545 | GEO
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.
2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress
Project description:Cerebral vascular malformations (CCM) are primarily found within brain, where they result in increased risk for stroke, seizures and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier (BBB) formed by the brain neurovascular unit, and recent studies suggest that loss of CCM genes causes disruptions of BBB integrity as the inciting event for the development of CCM. CCM lesion is proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling in the subclass of brain EC/EPC for the CCM lesion initiation and progression are unclear. Here we employed single-cell RNA-sequencing (scRNA-seq) analyses in early stages of the brain EC-specific Ccm3 deletion (Pdcd10BECKO) microvessels and identified a unique EPC cluster with high stem cell markers but low BBB-associated genes. mTORC1, but not mTORC2, is activated in mouse and human CCM lesions and EPCs. Mechanistic studies suggest that CCM3 suppresses Cav1/caveolae-mediated cellular trafficking and complex formation of the mTORC1 signaling proteins. Genetic deficiency of Raptor (mTORC1), but not of Rictor (mTORC2), prevents CCM lesion formation in the Pdcd10BECKO model. Importantly, mTORC1 pharmacological inhibitor Rapamycin ameliorate the CCM pathogenesis in the Pdcd10BECKO mice, by suppressing lesion-forming EPC expansion while enhancing BBB maturation. Our data suggest that CCM3 is critical for maintaining BBB integrity, and CCM3 loss-induced mTORC1 signaling in brain EPCs initiate the CCM pathogenesis.
2024-06-12 | GSE246598 | GEO
Project description:The PI3K-AKT-mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit likely due to their lack of effects on 4E-BP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multi-omic analysis showed extensive effects of the bi-steric inhibitors in comparison to rapamycin. De novo purine synthesis was markedly and selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a novel therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.
2023-11-08 | GSE236742 | GEO