Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA314322 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Most human cancers arise from stem/progenitor cells by sequential accumulation of genetic/epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here we show that a single p53 mutation, despite causing no defect in mouse brain, promoted neural stem/progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas/glioblastomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem-cell niche. Unexpectedly, Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53-mutant Sonic Hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and developing brain, promoting malignant gliomas/glioblastoma and suppressing SHH-medulloblastoma formation, respectively.
2021-06-15 | GSE115840 | GEO
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
Project description:Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma
| PRJNA476243 | ENA
Project description:DDX3X is frequently mutated in the WNT and SHH subtypes of medulloblastoma Ð the commonest malignant childhood brain tumor. But whether DDX3X functions as a medulloblastoma oncogene or tumor suppressor gene is not known. Here we show that Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling. In mice predisposed to Wnt or Shh-medulloblastoma Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHH-medulloblastomas normally arise only in the lower and upper rhombic lips respectively. Deletion of Ddx3x relived this lineage restriction enabling both medulloblastoma subtypes to arise in either germinal zone. Thus DDX3X is a medulloblastoma tumor suppressor that regulates hindbrain development and restricts the competence of cell lineages to form medulloblastoma subtypes.
2020-03-19 | GSE147178 | GEO
Project description:DDX3X is frequently mutated in the WNT and SHH subtypes of medulloblastoma Ð the commonest malignant childhood brain tumor. But whether DDX3X functions as a medulloblastoma oncogene or tumor suppressor gene is not known. Here we show that Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling. In mice predisposed to Wnt or Shh-medulloblastoma Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHH-medulloblastomas normally arise only in the lower and upper rhombic lips respectively. Deletion of Ddx3x relived this lineage restriction enabling both medulloblastoma subtypes to arise in either germinal zone. Thus DDX3X is a medulloblastoma tumor suppressor that regulates hindbrain development and restricts the competence of cell lineages to form medulloblastoma subtypes.
2020-03-19 | GSE147069 | 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. Gene expression in PVAT of RictoraP2KO mice was compared to controls (Rictorfl/fl) mice.
2015-07-05 | E-GEOD-67077 | 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:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine Shh medulloblastoma, acutely induced at postnatal stages of development.
2017-11-22 | GSE107253 | 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.
| MSV000084310 | MassIVE