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Regulation of Rat Hepatic Translation by mTOR

ABSTRACT: Our strategy was to manipulate mTOR signaling in vivo, then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the non-proliferative growth model of refeeding after a period of fasting, and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from pre-term fetal rats (embryonic day 19-20) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE67022 | GEO | 2015/06/01

SECONDARY ACCESSION(S): PRJNA278738

REPOSITORIES: GEO

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Persistent Effect of mTOR Inhibition on Preneoplastic Foci Progression and Gene Expression in a Rat Model of Hepatocellular Carcinoma

Project description:We previously identified the mTOR pathway as critical to progenitor cell proliferation in a model of liver injury, we investigated the temporal activation of mTOR signaling in a rat model of hepatic carcinogenesis. The model employed chemical carcinogens and partial hepatectomy to induce progenitor marker-positive HCC. Rats were administered the mTOR inhibitor rapamycin for a three week period and liver harvested one month following cessation of rapamycin treatment. Short-term rapamycin treatment resulted in a significant reduction of focal lesion burden. Microarray analysis was performed to characterize the gene expression signature of persistent focal lesions in the rapamcyin and placebo treated animals. This analysis revealed a persistent effect of short-term mTORC1 inhibition on gene expression that resulted in a genetic signature reminiscent of normal liver.

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Deletion of mTOR in liver epithelial cells enhances hepatic metastasis of colon cancer

Project description:Activation of the mechanistic target of rapamycin (mTOR) pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established liver epithelial cell (LEC)-specific knockout (KO) of mTOR (mTORLEC) mice. We used these mice to characterize the growth of colorectal liver metastases with or without partial hepatectomy to model different clinical settings. Although the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared with wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-ĸB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-ĸB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in LECs. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage testing whether anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitors for cancer therapy.

2023-01-05 | PXD019998 | Pride

Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

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Hepatectomy sham surgery 1h

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mTOR

Project description:mTOR

| PRJEB9498 | ENA

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

Project description:Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results show that constitutive mTORC1 activation caused by abrogation of TSC2 increases H3K27me3 but not H3K4me3 or H3K9me3, via 4E-BPs-mediated induction of EZH2 protein levels. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects.

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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

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2023-10-13 | GSE242949 | GEO

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