Expression data from MOLM-14 human acute myeloid leukemia cell line after mTORC1 inhibition by rapamycin
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE95172 | GEO | 2017/08/14
SECONDARY ACCESSION(S): PRJNA376267
REPOSITORIES: GEO
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Project description:AMPK activation by GSK621 induces cell death in acute myeloid leukemia. Surprisingly, we found that mTORC1 inhibition with rapamycin protects cells against GSK621-induced cytotoxicity. A genome-wide gene expression assay was performed to understand the molecular basis of this phenotype.
2016-04-22 | GSE68209 | GEO
Project description:Liver from RICTOR knockout mice show normal levels of mTORC1 signaling in response to refeeding. With this experiment we sought to compare the effects of Rictor depletion to the effects of mTORC1 inhibition by rapamycin in liver from mice that were fasted and refed. Mice were either fasted for 24hr (n=5), or fasted for 22hr then treated with either 10mg/kg rapamycin suspended in 0.9% NaCl and 2% ethanol at a concentration of 1mg/ml (547mM), or vehicle only. After an additional 2 hr, one group of mice (0 hr time, n=3) was sacrificed, the liver immediately removed, and flash frozen in liquid nitrogen. The remaining mice were given ad libitum access to food and sacrificed after 3hr (n=3), 6hr (n=3), or 12 hr (n=3). Two other nonfasted groups of mice (n=2) were injected with either vehicle or rapamycin and sacrificed after 24hr. Submitter cannot locate the CEL files.
2013-09-23 | E-GEOD-46582 | biostudies-arrayexpress
Project description:Liver from RICTOR knockout mice show normal levels of mTORC1 signaling in response to refeeding. With this experiment we sought to compare the effects of Rictor depletion to the effects of mTORC1 inhibition by rapamycin in liver from mice that were fasted and refed.
2013-09-23 | GSE46582 | 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 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:Gp130 receptor engagement on neoplastic cells provides a link by which an inflammatory microenvironment facilitates tumour promotion. Although hyperactivation of the gp130-dependent Stat3 signalling node is commonly observed in solid tumours, Stat3 remains a challenging therapeutic target. To mimic excessive Stat3 signalling, we molecularly validate the gp130FF mouse as a preclinical model for inflammation-associated intestinal-type gastric cancer (IGC), with aberrant mammalian target of rapamycin (mTOR) pathway activity as shared feature. Accordingly, administration of the mTorc1 inhibitor RAD001 reversibly reduced IGC burden in gp130FF mice and suppressed colitis-associated cancer in wild-type mice. Since the therapeutic effect of RAD001 occurs independently of Stat3 hyperactivation, which is also dispensable for gp130-dependent engagement of the PI3K/Akt/mTorc1 pathway, we conclude that mTorc1 signalling limits tumour promoting Stat3 activity The mouse whole-genome gene expression profiling was performed on Illumina's MouseWG-6 v2.0 Expression BeadChips for 24 mice, with 8 mice in each group (gp130WT antral tissue, gp130FF unaffected antral tissue and gp130FF tumour tissue).
2013-01-29 | E-GEOD-35808 | biostudies-arrayexpress
Project description:Purpose: Despite demonstrating that the overall effect of long-term rapamycin-treatment is overwhelmingly positive in aging skeletal muscle, we observed muscle-specificity in the responsiveness to rapamycin, leading us to hypothesize that the primary drivers of age-related muscle loss and therefore effective intervention strategies may differ between muscles. To address this question and dissect the key signaling nodes associated with mTORC1-driven muscle aging, we created a comprehensive multi-muscle gene expression atlas in adult, sarcopenic and rapamycin-treated mice using RNA-seq. Methods: To examine the impact of long-term rapamycin treatment, male C57BL/6 mice were fed encapsulated rapamycin incorporated into a standardized AIN93M diet at 42 ppm (i.e. mg per kg of food), corresponding to a dose of ~4 mg·kg-1·day-1, from 15- to 30-months of age. This dose of rapamycin has been shown to extend lifespan maximally in male C57BL/6 mice. We performed RNA-seq on gastrocnemius (GAS), tibialis anterior (TA), triceps brachii (TRI) and soleus (SOL) muscles from each of six mice for 10m, 30m and 30mRM groups. The four muscle types were chosen to encompass fore- and hindlimb locations (e.g. TRI and GAS); slow and fast contraction properties (e.g. SOL and GAS); anterior and posterior positioning (e.g. TA and GAS) and the extent of protection by rapamycin (TA and TRI: protected; SOL: partiallly protected; GAS: not protected). Results: Age-related gene expression changes were remarkably consistent across the four different muscles, varying only in magnitude. Despite having the smallest age-related muscle loss of the four muscles, TA had the strongest age-related gene expression response which was associated with an increased reinnervation response. Despite the strong between-muscle commonality of age-related changes, gene expression responses to prolonged rapamycin treatment differed substantially between muscles. Rapamycin partially reversed many age-related changes in mRNA expression in the TA and TRI, but not in SOL or GAS muscle. Principle component analysis (PCA) showed that rapamycin had common 'anti-aging' effects on all muscles, while also exerting muscle-specific pro-aging effects on muscles not protected by rapamycin. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.
2020-06-19 | GSE139204 | GEO
Project description:Background: Mechanistic target of rapamycin (mTOR) is a nodal serine/threonine protein kinase critical for the control of fundamental cellular processes. Dysregulated mTOR signalling has been shown in cancer, COPD and idiopathic pulmonary fibrosis (IPF). mTOR forms the catalytic subunit of 2 protein complexes: mTORC1 and mTORC2 which differ in upstream inputs, downstream effects and sensitivity to the allosteric inhibitor rapamycin. Aim: To compare the effects of the mTORC1 inhibitor rapamycin with an ATP-competitive inhibitor of mTORC1/2, AZD8055, on TGFβ1 induced transcriptional responses during myofibroblast differentiation by RNA-Seq analysis. Methods: Primary human lung fibroblasts were treated with TGFβ1 for 24h to induce myofibroblast differentiation and extra cellular matrix (ECM) production in the presence of rapamycin or AZD8055. Fibroblasts were also treated with rapamycin or AZD8055 without TGFβ1. Total mRNA was analysed by RNA-Seq. Results: On a global transcriptomic level, TGFβ1 significantly affected the expression of ~4,200 genes by more than 1.5 fold, of which ~1,100 changes were reversed by pan-mTORC1/2 inhibition, while being insensitive to rapamycin. Only 15 gene changes were reversed exclusively by rapamycin. Analysis of the rapamycin-insensitive, mTOR sensitive myofibroblast transcriptome revealed ECM-receptor interaction, metabolism and actin cytoskeleton regulation as major affected pathways. Conclusions: Our data support the conclusion that therapeutic approaches aimed at interfering with TGFb1 induced myofibroblast differentiation and ECM production require dual mTOR1/2 inhibition and may, in part, explain the lack of clinical efficacy of everolimus in the context of IPF.
2019-05-01 | GSE102674 | GEO
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2011-07-01 | E-GEOD-30315 | biostudies-arrayexpress