Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth

Parent, Romain; Kolippakkam, Deepak; Booth, Garrett C.

doi:10.1158/0008-5472.can-06-3640

Cited by 36 publications

(32 citation statements)

References 45 publications

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“…Interestingly, while inhibition of mTOR/p63/ Notch inhibits the differentiation of normal cells, sustained activation of mTOR impairs cell differentiation through overactivation of the p63/Jagged/Notch cascade. This observation is consistent with a recent report showing that differentiation of HepaRG cells into hepatocyte-like cells is attenuated by expression of an activated mutant mTOR (59). Given the dose-dependent binary effects of both mTOR and Notch on cell differentiation, the functioning of Notch appears to depend on the status of mTOR activity.…”

Section: Discussionsupporting

confidence: 92%

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Ma¹,

Meng²,

Kwiatkowski³

et al. 2010

J. Clin. Invest.

214

217

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The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

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Section: Discussionsupporting

confidence: 92%

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Ma¹,

Meng²,

Kwiatkowski³

et al. 2010

J. Clin. Invest.

214

217

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“…In the yeast model, rapamycin negatively affects both the steady state and polysome-associated mRNA levels of genes involved in RNA processing and ribosome biogenesis together with the proteasome (9). However, in reports regarding vertebrates, the effects of rapamycin on ribosomes have been attributed predominantly to alterations in the polysome-associated mRNA pool (34,35). The comparative transcriptomics of the present study indicated that, in both zebrafish and mice, steady state mRNA levels of ribosomal subunits were upregulated coordinately.…”

Section: Discussionmentioning

confidence: 48%

Functionally conserved effects of rapamycin exposure on zebrafish

Sucularli¹,

Shehwana²,

Kuscu³

et al. 2016

Molecular Medicine Reports

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Abstract. Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase important in cell proliferation, growth and protein translation. Rapamycin, a well-known anti-cancer agent and immunosuppressant drug, inhibits mTOR activity in different taxa including zebrafish. In the present study, the effect of rapamycin exposure on the transcriptome of a zebrafish fibroblast cell line, ZF4, was investigated. Microarray analysis demonstrated that rapamycin treatment modulated a large set of genes with varying functions including protein synthesis, assembly of mitochondrial and proteasomal machinery, cell cycle, metabolism and oxidative phosphorylation in ZF4 cells. A mild however, coordinated reduction in the expression of proteasomal and mitochondrial ribosomal subunits was detected, while the expression of numerous ribosomal subunits increased. Meta-analysis of heterogeneous mouse rapamycin microarray datasets enabled the comparison of zebrafish and mouse pathways modulated by rapamycin, using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analysis. The analyses demonstrated a high degree of functional conservation between zebrafish and mice in response to rapamycin. In addition, rapamycin treatment resulted in a marked dose-dependent reduction in body size and pigmentation in zebrafish embryos. The present study is the first, to the best of our knowledge, to evaluate the conservation of rapamycin-modulated functional pathways between zebrafish and mice, in addition to the dose-dependent growth curves of zebrafish embryos upon rapamycin exposure.

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“…However, the dual PI3K-mTOR inhibitor, NVP-BEZ235 effectively reverted the decrease of fatty acid oxidation both in vitro and in vivo (Evert et al, 2012). Sustained mTOR activity may contribute to the development of steatosis in the hepaRG cell line by impairing lipid homeostasis via decreasing the expression of the transcription factors PPARα and PPARδ (Parent et al, 2007). The treatment with rapamycin in the skeletal muscle cells increased fatty acid oxidation by increasing activities of CPT I and II both in vivo and in vitro (Sipula et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Liu

Han

Wan

et al. 2016

Animal

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Phosphatidylinositol-3 kinases (PI3K)-Protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway plays an important role in the synthesis and secretion of triacylglycerol. However, the mechanism of PI3K-Akt-mTOR pathway in regulating lipid metabolism of goose liver was poorly understood. The purpose of this study was to determine how PI3K-Akt-mTOR pathway regulating lipid metabolic homeostasis in goose hepatocytes. Goose primary hepatocytes were treated with different PI3K-Akt-mTOR signal inhibitors (LY294002, rapamycin and NVP-BEZ235) for 24 h. The results showed that these inhibitors evidently inhibited PI3K-Akt-mTOR downstream signaling. Meanwhile, these PI3K-Akt-mTOR inhibitors reduced intracellular lipid accumulation, decreased the mRNA expression and protein content of genes involved in the de novo fatty acid synthesis, while increased the transcriptional and protein level of key factors involved in fatty acid oxidation and very low density lipoprotein (VLDL) assembly and secretion. Conclusion: These findings suggested that the reduction of lipids accumulation induced-by inhibiting PI3K-Akt-mTOR pathway was closely linked to the decrease of lipogenesis, the increase of fatty acids oxidation, and the increase of VLDL assembly and secretion in goose hepatocytes.

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Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth

Abstract: The mammalian target of rapamycin

Cited by 36 publications

References 45 publications

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Functionally conserved effects of rapamycin exposure on zebrafish

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

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