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Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulation of the primary human trophoblast cell transcriptome

ABSTRACT: Differential gene expression following the silencing of rictor and raptor to identify genes regulated by mTORC2 in primary human trophoblast (PHT) cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185949 | GEO | 2021/10/16

REPOSITORIES: GEO

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Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulation of the primary human trophoblast cell transcriptome

Project description:Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulation of the primary human trophoblast cell transcriptome

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Rictor/mTORC2 signaling has opposing functions in adult glioma and childhood SHH medulloblastoma

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

The lipid handling capacity of subcutaneous fat is programmed by mTORC2 during development

Project description:Obesity causes type 2 diabetes, cardiovascular diseases, NAFLD, and cancer, but all fat is not equal as subcutaneous white adipose tissue (SWAT) is more metabolically favorable than visceral fat. Here, we investigate mTORC2 function in SWAT growth by deleting its essential subunit Rictor in SWAT precursor cells and examining its effect on adipocyte differentiation and tissue development. We found that Rictor/mTORC2 is not required for SWAT preadipocyte differentiation per se; however, SWAT preadipocytes differentiating without Rictor cannot fully induce the lipid storage transcriptional program. In vivo, this results in smaller adipocytes, reduced SWAT size, lipid re-distribution to visceral and brown fat, and gender-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes PPARg activity towards specific lipid metabolism genes independently of ChREBP, but in coordination, to set the lipid handling capacity of SWAT. Further exploring this pathway may uncover new strategies to stimulate lipid storage in more metabolically favorable SWAT.

2020-10-06 | GSE146470 | GEO

Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

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

Enhancing Acsl4 in absence of mTORC2/Rictor drove β-cell dedifferentiation via inhibiting FoxO1 and promoting ROS production

Project description:We here identified Acsl4, a new target of mTORC2, could rescue the impaired β cell proliferation, but not deficient insulin secretion induced by loss of Rictor.

2022-09-26 | GSE138014 | GEO

Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2).

Project description: Not available

| S-EPMC3868844 | biostudies-literature

Integrin-α10-dependency defines a novel therapeutic strategy targeting RAC and mTORC2 for metastatic myxofibrosarcoma

Project description:Analysis of U133A microarray data from 64 primary high-grade myxofibrosarcoma tumors identified ITGA10 as the gene most significantly associated with distant metastasis and poor disease-specific survival. Further investigation using shRNA knockdown identifies the TRIO-RAC-PAK and RICTOR-mTORC2 pathways as important downstream signaling pathways for ITGA10.

2016-11-29 | GSE72545 | GEO

Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

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

Expression data from mouse model using targeted deletion of hepatic RICTOR (Albumin-Cre Rictor LoxP/LoxP)

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

mTORC2/Akt Activation in Adipocytes is Required for Mycobacterium tuberculosis Derived Inflammation in Adipose Tissue

Project description:The association between type 2 DM (T2DM) and susceptibility to tuberculosis (TB) is well recognized. Patients with DM have 2-3 fold increased susceptibility to TB, treatment is longer and the outcome is worse than in non-diabetic TB patients. Here, we report that aerosol infection with M. tuberculosis is followed by leukocyte infiltration and proliferation, and expression of inflammatory markers in adipose tissue of lean mice leading to disrupted lipid metabolism and the induction of adipocyte hypertrophy. RNA-sequencing (RNAseq) in whole pgWAT adipose tissue at 8 wk after aerosol challenge revealed an upregulation of genes that were associated with antigen presentation, Th1 and type-1 interferon response, indicated the induction of T cell activation. This was found to be due to activated mTORC2/Akt signaling. By depleting Rictor (mTORC2 subunit) in adipocytes we noticed the restoration of inflammation and cell hypertrophy. Our study suggests that TB-induced inflammation in the adipose tissue is associated with improved glucose tolerance and is mediated by mTORC2/Akt pathway.

2019-01-01 | GSE106611 | GEO

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