Effect of depletion of Rictor on gene expression during 3% DSS treatment of colonic epithelial cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250391 | GEO | 2025/12/18
REPOSITORIES: GEO
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| GSE250391_gene_count.txt.gz | Txt | |||
| GSE250391_gene_fpkm.txt.gz | Txt |
Items per page: 5 1 - 3 of 3 |
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Project description:Recent work using mouse models has revealed that mTORC2, which unlike mTORC1 is not acutely sensitive to rapamycin, plays a key role in the regulation of organismal physiology. The substrates and pathways regulated by mTORC2 are at present relatively unknown Using a mouse model with a targeted deletion of hepatic RICTOR, we investigated the loss of mTORC2 on the murine liver transcriptome Rictor floxed (RKO) and control mice (n=4 per group) were fasted overnight, refed for 3 hr, then sacrificed. Livers were removed, rinsed in PBS, and flash frozen in liquid nitrogen. RNA was extracted and hybridized to Affymetrix Genechip Mouse Gene 1.0 ST arrays
2013-09-23 | E-GEOD-46515 | biostudies-arrayexpress
Project description:Nearly 50% of cutaneous melanomas carry activating mutations on the BRAF oncogene, and the combination of BRAF- and MEK-inhibitors (BRAF/MEKi) is frequently used for their clinical management. One major drawback of BRAF/MEKi targeted therapy is the rapid development of therapeutic resistance, which can occur via multiple mechanisms, including the metabolic rewiring of cancer cells that often involves the upregulation of mitochondrial bionergetics and NAD+ biosynthetic pathways. mTORC2 is a signaling complex that requires the presence of its essential RICTOR subunit to play its regulatory functions in cell growth and metabolism. mTORC2 is believed to play mostly pro-oncogenic roles in several tumor types, including melanoma. However, bioinformatics analysis of TCGA melanoma patients’ database revealed that low RICTOR levels in tumors correlate with an overall worse clinical outcome. GSEA analysis of low-RICTOR tumors evidenced also a gene expression signature suggestive of activation of mitochondrial energy producing pathways. On these bases, we have hypothesized that inhibition of mTORC2 activity may render BRAFV600E melanoma cells resistant to BRAFi/MEKi. We show here that RICTOR/mTORC2-deficient cells are intrinsically tolerant to BRAFi/MEKi, and anticipate the onset of resistance to BRAFi after sustained drug exposure both in vitro and in vivo, indicating that mTORC2 activity normally opposes the acquisition of targeted therapy resistance in BRAFV600E melanomas. Mechanistically, RICTOR-deficient cells show an enhanced mitochondrial respiratory potential and increased expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, the rate-limiting enzyme of NAD+ salvage pathway, and pharmacological inhibition of these processes in RICTOR-deficient cells is sufficient to restore sensitivity to BRAFi. Thus, our work identifies a novel role for mTORC2 in favoring the responses of BRAF-mutated melanoma cells to targeted therapy, and suggest that the evaluation of the intratumor level of RICTOR may help to predict the responses of melanoma patients to these treatments.
2024-05-23 | PXD045346 | Pride
Project description:The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to regulating glucose and lipid metabolism. In the perivascular adipose tissue (PVAT) mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (RictoraP2KO) mice generated by using adipocyte protein-2 gene promoter-driven CRE recombinase to delete Rictor. 24 hour mean arterial pressure (MAP) was increased in RictoraP2KO mice, and the physiologic decline in MAP during the dark period impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides (NPs) and NP receptor expression in adipocytes. Moreover, clock gene expression was dampened or phase-shifted in PVAT. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus (SCN), though Rictor gene expression was also lower in brain of RictoraP2KO mice. Thus, the present study underscores the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes and brain to tune physiological outcomes such as blood pressure and locomotion. Gene expression in PVAT of RictoraP2KO mice was compared to controls (Rictorfl/fl) mice.
2015-07-05 | E-GEOD-67077 | biostudies-arrayexpress
Project description:Recent work using mouse models has revealed that mTORC2, which unlike mTORC1 is not acutely sensitive to rapamycin, plays a key role in the regulation of organismal physiology. The substrates and pathways regulated by mTORC2 are at present relatively unknown Using a mouse model with a targeted deletion of hepatic RICTOR, we investigated the loss of mTORC2 on the murine liver transcriptome
2013-09-23 | GSE46515 | GEO
Project description:We provide evidence that IFN-induced Stat-activation is defective in cells with targeted disruption of the Rictor gene, whose protein product is a key element of mTOR complex 2 (mTORC2). Our studies show that transient or stable knockdown of Rictor leads to decreased expression of several IFN-inducible genes that mediate important biological functions, including antiproliferative and pro-apoptotic responses. Rictor+/+ and Rictor-/- MEFs were treated with 2500 U/ml of mouse IFNα for 24 hours
2014-01-28 | E-GEOD-47896 | biostudies-arrayexpress
Project description:The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to regulating glucose and lipid metabolism. In the perivascular adipose tissue (PVAT) mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (RictoraP2KO) mice generated by using adipocyte protein-2 gene promoter-driven CRE recombinase to delete Rictor. 24 hour mean arterial pressure (MAP) was increased in RictoraP2KO mice, and the physiologic decline in MAP during the dark period impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides (NPs) and NP receptor expression in adipocytes. Moreover, clock gene expression was dampened or phase-shifted in PVAT. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus (SCN), though Rictor gene expression was also lower in brain of RictoraP2KO mice. Thus, the present study underscores the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes and brain to tune physiological outcomes such as blood pressure and locomotion.
2015-07-05 | GSE67077 | GEO
Project description:Background Main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF- mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to define in this context the specific role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit and regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing the TCGA MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF V600E MM cell lines on their response to BRAF/MEKi in vitro. We performed a proteomic screening to identify proteins modulated by changes in RICTOR expression and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results We found that low RICTOR levels in MM correlate with an overall worse clinical outcome. GSEA of low- RICTOR tumors revealed a gene expression signature suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy producing pathway. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAFi/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. In RICTOR- depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, while their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils a novel tumor suppressing role for mTORC2 in the responses of BRAF V600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low- RICTOR tumors. Importantly, our findings support the concept that the evaluation of intra-tumor RICTOR levels in MM has a prognostic value, and may help predicting the response of patients to targeted therapy.
2024-06-22 | PXD050614 | Pride
Project description:Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through Nrf2-dependent, AKT-independent signaling and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role of Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer.
2025-03-21 | GSE120743 | GEO
Project description:Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 has been shown to be important for regulating BAT metabolism, yet its mechanism of activation is not known, nor are the identities of its downstream effectors. In this study, we apply proteomics to investigate the role of mTORC2 in brown adipocytes. To assess the role of mTORC2 in brown adipocytes, we compare wild-type controls to isogenic cells with an induced knockout of the mTORC2-specific subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30 minute time course, and measuring the proteomes and phosphoproteomes. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation, suggesting increased interferon-like signaling. We observe significant differences to basal phosphorylation including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells and Rictor-null mouse BAT, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. And finally, we observe a general dampening of the insulin signaling response in Rictor-iKO cells. Some sites exhibit significant dependence on RICTOR, including an AKT substrate site on ATP citrate lyase, which could partially explain the previously-observed RICTOR dependence of de novo lipogenesis from glucose in BAT.
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Project description:Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Rictor/mTORC2 deletion inhibits Akt signaling, causing a significant delay in p53-mutant driven glioma formation. Unexpectedly, Rictor/mTORC2 loss promotes p53-mutant driven medulloblastomas with unique features of pediatric SHH medulloblastoma. Mechanistically, Rictor/mTORC2 loss inhibits the generation of glioma precursor cells from neural stem/progenitor cells in the adult brain, while causing a delay in differentiation of granule cell precursors in the developing brain, a cell-of-origin of SHH medulloblastoma.
2018-06-01 | GSE78895 | GEO