Expanding mTOR signaling

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Research (Impact Factor: 12.41). 09/2007; 17(8):666-81. DOI: 10.1038/cr.2007.64
Source: PubMed


The mammalian target of rapamycin (mTOR) has drawn much attention recently because of its essential role in cell growth control and its involvement in human tumorigenesis. Great endeavors have been made to elucidate the functions and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental biological processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including growth factors, nutrients, energy levels, and cellular stress. The significance of mTOR has been highlighted most recently by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells but also further complicate the regulation network. Thus, it is now even more critical that we precisely understand the underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the mTOR signaling pathway. In this review, we will discuss different mTOR-associated proteins, the regulation of mTOR complexes, and the consequences of mTOR dysregulation under pathophysiological conditions.

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    • "However, recent data suggested that cellular outcome in tumor cell treatment cannot be predicted by changes in the phosphorylation status of AKT as induction of its phosphorylation in the presence of the broad anti-tumor agent everolimus (RAD0019) has been shown to occur as a results of mTORC1 (rapamycin-sensitive kinase complex containing raptor) inhibition in a rictor-dependent manner [46]. Further supporting this, a negative feedback loop has been described, where mTOR/S6K1 activation results in PI3K signaling inhibition by suppressing the insulin receptor-dependent cascade [47] [48] [49]. Hence, it remains to be determined whether the anti-proliferative response in cells incubated with PCP is accompanied by mTORC1 inhibition and whether suppression of AKT phosphorylation at S473 can be induced by rictor down-regulation. "
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    ABSTRACT: Pancreatic adenocarcinoma is one of the deadliest human solid tumors in the developed countries characterized by high resistance towards chemotherapeutic treatment. We have previously shown that silencing of the pro-survival protein kinase CK2 by RNA interference contributes to enhance the cytotoxicity of the chemotherapeutic agent 2’,2’-difluoro 2’-deoxycytidine (gemcitabine). Initial experiments showed that pentachlorophenol (PCP) inhibits CK2 and induces cell death in human pancreatic cancer cell lines. We report here evidence that exposure of this type of cells to PCP induces caspase-mediated apoptosis, inhibition of the lysosome cysteine protease cathepsin B and mitochondrial membrane depolarization. Beside cellular inhibition of CK2, the analysis of signaling pathways de-regulated in pancreatic cancer cells revealed that PCP causes decreased phosphorylation levels of NF-κB/p65, suppresses its nuclear translocation and leads to activation of JNK-mediated stress response. Surprisingly, exposure to PCP results in increased phosphorylation levels of AKT at the canonical S473 and T308 activation sites supporting previous data showing that AKT phosphorylation is not predictive of tumor cell response to treatment. Taken together, our study provides novel insights into the effects induced by the exposure of pancreatic cancer cells to chlorinated aromatic compounds posing the basis for more advanced studies in vivo.
    Toxicology Reports 11/2014; 1. DOI:10.1016/j.toxrep.2014.10.027
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    • "Genetic studies in Drosophila and mice (15–18) have also shown that mTOR activity affects cell size, which is a key parameter that governs entry into the cell cycle (19). mTOR also integrates diverse upstream signals, including amino acid- and energy stress-sensing, to regulate cell proliferation, growth and survival (20,21). Notably, it has also been confirmed that the aberrant stimulation of the PI3K-AKT-mTOR pathway is associated with a poor prognosis in ovarian cancer patients (22). "
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    ABSTRACT: Pien Tze Huang (PZH) is a well-known Chinese medicine that has been used as a therapeutic drug in the treatment of a number of diseases, such as hepatocellular carcinoma and colon cancer. However, few studies have analyzed the effects of PZH on ovarian cancer cell proliferation. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays, cell cycle and apoptosis rate analyses and western blotting were conducted to investigate the effects of PZH on the proliferation rate of ovarian cancer cells and its potential molecular pathway. The results showed that PZH inhibits the proliferation of the human ovarian cancer OVCAR-3 cell line by blocking the progression of the cell cycle from the G1 to S phase, however, PZH did not induce OVCAR-3 cell apoptosis. Increased PZH concentration may downregulate the expression of AKT, phosphorylated (p)-AKT, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the OVCAR-3 cell line. In addition, it was observed that PZH may suppress the protein expression of cyclin-dependent kinase (CDK)4 and CDK6. Overall, the results of the present study indicated that PZH may inhibit ovarian cancer cell proliferation by modulating the activity of the AKT-mTOR pathway.
    Oncology letters 06/2014; 7(6):2047-2052. DOI:10.3892/ol.2014.1989 · 1.55 Impact Factor
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    • "Branched-chain amino acids such as leucine have been found to activate mTOR complex 1 (mTORC1) via inhibition of TSC1/TSC2 [32], [33]. To determine whether UA inhibits leucine-stimulated mTOR signaling by targeting TSC1/2, we examined whether knockout of TSC1/2 affects the ability of UA to suppress mTORC1 signaling. "
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    ABSTRACT: Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.
    PLoS ONE 04/2014; 9(4):e95393. DOI:10.1371/journal.pone.0095393 · 3.23 Impact Factor
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