UNIPROT:P42345 - FACTA Search

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Query: UNIPROT:P42345 (mTOR)
26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that late in a simian virus 40 (SV40) infection in CV-1 cells, there are significant decreases in phosphorylations of two mammalian target of rapamycin (mTOR) signaling effectors, the eIF4E-binding protein (4E-BP1) and p70 S6 kinase (p70S6K). The hypophosphorylation of 4E-BP1 results in 4E-BP1 binding to eIF4E, leading to the inhibition of cap-dependent translation. The dephosphorylation of 4E-BP1 is specifically mediated by SV40 small t antigen and requires the protein phosphatase 2A binding domain but not an active DnaJ domain. Serum-starved primary African green monkey kidney (AGMK) cells also showed decreased phosphorylations of mTOR, 4E-BP1, and p70S6K at late times in infection (48 h postinfection [hpi]). However, at earlier times (12 and 24 hpi), in AGMK cells, phosphorylated p70S6K was moderately increased, correlating with a significant increase in phosphorylation of the p70S6K substrate, ribosomal protein S6. Hyperphosphorylation of 4E-BP1 at early times could not be determined, since hyperphosphorylated 4E-BP1 was present in mock-infected AGMK cells. Elevated levels of phosphorylated eIF4G, a third mTOR effector, were detected in both CV-1 and AGMK cells at all times after infection, indicating that eIF4G phosphorylation was induced throughout the infection and unaffected by small t antigen. The data suggest that during SV40 lytic infection in monkey cells, the phosphorylations of p70S6K, S6, and eIF4G are increased early in the infection (12 and 24 hpi), but late in the infection (48 hpi), the phosphorylations of mTOR, p70S6K, and 4E-BP1 are dramatically decreased by a mechanism mediated, at least in part, by small t antigen.
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PMID:Effects of simian virus 40 large and small tumor antigens on mammalian target of rapamycin signaling: small tumor antigen mediates hypophosphorylation of eIF4E-binding protein 1 late in infection. 1589 Sep 27

Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFalpha) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel-Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.
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PMID:Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. 1595 68

A series of 30 N10-substituted phenoxazines were synthesized and screened as potential inhibitors of Akt. In cellular assays at 5 mum, 17 compounds inhibited insulin-like growth factor 1 (IGF-I)-stimulated phosphorylation of Akt (Ser-473) by at least 50% but did not inhibit IGF-I-stimulated phosphorylation of Erk-1/2 (Thr-202/Tyr-204). Substitutions at the 2-position (Cl or CF3) did not alter inhibitory activity, whereas N10-substitutions with derivatives having acetyl (20B) or morpholino (12B) side chain lost activity compared with propyl or butyl substituents (7B and 14B). Inhibition of Akt phosphorylation was associated with the inhibition of IGF-I stimulation of the mammalian target of rapamycin phosphorylation (Ser-2448 and Ser-2481), phosphorylation of p70 S6 kinase (Thr-389), and ribosomal protein S6 (Ser-235/236) in Rh1, Rh18, and Rh30 cell lines. The two most potent compounds 10-[4'-(N-diethylamino)butyl]-2-chlorophenoxazine (10B) and 10-[4'-[(beta-hydroxyethyl)piperazino]butyl]-2-chlorophenoxazine (15B) (in vitro, IC50 approximately 1-2 microM) were studied further. Inhibition of Akt phosphorylation correlated with inhibition of its kinase activity as determined in vitro after immunoprecipitation. Akt inhibitory phenoxazines did not inhibit the activity of recombinant phosphatidylinositol 3'-kinase, PDK1, or SGK1 but potently inhibited the kinase activity of recombinant Akt and Akt deltaPH, a mutant lacking the pleckstrin homology domain. Akt inhibitory phenoxazines blocked IGF-I-stimulated nuclear translocation of Akt in Rh1 cells and suppressed growth of Rh1, Rh18, and Rh30 cells (IC50 2-5 microM), whereas "inactive" derivatives were > or = 10-fold less potent inhibitors of cell growth. In contrast to rapamycin analogs, Akt inhibitory phenoxazines induced significant levels of apoptosis under serum-containing culture conditions at concentrations of agent consistent with Akt inhibition. Thus, the cellular responses to phenoxazine inhibitors of Akt appear qualitatively different from the rapamycin analogs. Modeling studies suggest inhibitory phenoxazines may bind in the ATP-binding site, although ATP competition studies were unable to distinguish between competitive and noncompetitive inhibition.
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PMID:Identification of N10-substituted phenoxazines as potent and specific inhibitors of Akt signaling. 1600 6

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius not observed in rats with a sterile abscess. Inhibition is associated with an impaired mRNA translation initiation that can be ameliorated by elevating IGF-I but not insulin. The present study investigated the ability of IGF-I signaling to stimulate protein synthesis in gastrocnemius by accelerating mRNA translation initiation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Protein synthesis in gastrocnemius from septic rats was accelerated twofold by the addition of IGF-I (10 nM) to perfusate. IGF-I increased the phosphorylation of translation repressor 4E-binding protein-1 (4E-BP1). Hyperphosphorylation of 4E-BP1 in response to IGF-I resulted in its dissociation from the inactive eukaryotic initiation factor (eIF) 4E.4E-BP1 complex. Assembly of the active eIF4F complex (as assessed by the association eIF4G with eIF4E) was increased twofold by IGF-I in the perfusate. In addition, phosphorylation of eIF4G and ribosomal protein S6 kinase-1 (S6K1) was also enhanced by IGF-I. Activation of mammalian target of rapamycin, an upstream kinase implicated in phosphorylating both 4E-BP1 and S6K1, was also observed. Thus the ability of IGF-I to accelerate protein synthesis during sepsis may be related to a stimulation of signaling to multiple steps in translation initiation with an ensuing increased phosphorylation of eIF4G, eIF4E availability, and S6K1 phosphorylation.
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PMID:IGF-I stimulates protein synthesis in skeletal muscle through multiple signaling pathways during sepsis. 1615 Aug 39

Eccentric contractions (EC) are known to result in muscle hypertrophy, potentially through activation of the Akt-mammalian target of rapamycin-p70 S6 kinase (p70S6K) signaling pathway. Previous work has also demonstrated that EC result in the opening of stretch-activated channels (SAC), and inhibition of these channels resulted in an attenuation of EC-induced muscle hypertrophy. The purpose of this study was to test the hypothesis that a known intracellular pathway directly associated with muscle hypertrophy is coupled to the opening of SAC. Specifically, we measured the activation of the Akt, GSK-3beta, p70S6K, and ribosomal protein S6 following a single bout of EC in the rat tibialis anterior (TA) muscle. The TA muscles performed four sets of six repetitions of EC. In vivo blockade of SAC was performed by a continuous oral treatment with streptomycin in the drinking water (4 g/l) or by intravenous infusion of 80 micromol/kg gadolinium (Gd3+). EC increased the degree of Akt and p70S6K phosphorylation in the TA muscle, whereas in animals in which SAC had been inhibited, there was a reduced capacity for EC to induce Akt or p70S6K phosphorylation. Accompanying this reduced activation of Akt and p70S6K was a failure to phosphorylate GSK-3beta or S6 when SAC were inhibited. The results from these data indicate the necessity of functional SAC for the complete activation of Akt and p70S6K pathway in response to EC.
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PMID:Inhibition of stretch-activated channels during eccentric muscle contraction attenuates p70S6K activation. 1617 99

The present study was conducted to determine the contribution of muscle protein synthesis to the prevention of anesthesia-induced hypothermia by intravenous administration of an amino acid (AA) mixture. We examined the changes of intraperitoneal temperature (Tcore) and the rates of protein synthesis (K(s)) and the phosphorylation states of translation initiation regulators and their upstream signaling components in skeletal muscle in conscious (Nor) or propofol-anesthetized (Ane) rats after a 3-h intravenous administration of a balanced AA mixture or saline (Sal). Compared with Sal administration, the AA mixture administration markedly attenuated the decrease in Tcore in rats during anesthesia, whereas Tcore in the Nor-AA group became slightly elevated during treatment. Stimulation of muscle protein synthesis resulting from AA administration was observed in each case, although K(s) remained lower in the Ane-AA group than in the Nor-Sal group. AA administration during anesthesia significantly increased insulin concentrations to levels approximately 6-fold greater than in the Nor-AA group and enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and ribosomal protein S6 protein kinase relative to all other groups and treatments. The alterations in the Ane-AA group were accompanied by hyperphosphorylation of protein kinase B and the mammalian target of rapamycin (mTOR). These results suggest that administration of an AA mixture during anesthesia stimulates muscle protein synthesis via insulin-mTOR-dependent activation of translation initiation regulators caused by markedly elevated insulin and, thereby, facilitates thermal accumulation in the body.
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PMID:Intravenous administration of amino acids during anesthesia stimulates muscle protein synthesis and heat accumulation in the body. 1635 75

We examined the role of the mammalian target of rapamycin (mTOR) in hepatic cell growth. To dissociate cell growth from cell proliferation, we employed an in vivo model of nonproliferative liver growth in rats, refeeding after 48 h of food deprivation. Starvation resulted in a decrease in liver mass, liver protein, and cell size, all of which were largely restored after 24 h of refeeding. Administration of the mTOR inhibitor, rapamycin, before the refeeding period partially inhibited the restoration of liver protein content. Refeeding was also associated with an increase in ribosomal protein S6 phosphorylation and phosphorylation of the eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1). 4E-BP1 phosphorylation was accompanied by a decrease in the abundance of the complex containing 4E-BP1 with eIF4E. These changes were prevented by rapamycin administration. However, association of eIF4E and eIF4G and eIF2alpha phosphorylation, both of which are stimulated by refeeding, were insensitive to rapamycin. The functional importance of these observations was confirmed by polysome fractionation, which showed that translation initiation of 5' oligopyrimidine tract-containing mRNAs, which encode ribosomal proteins, was inhibited by rapamycin, whereas translation of signal transducer and activator of transcription 1 (STAT1), a cap-dependent mRNA, was unaffected. The abundance of ribosomal proteins paralleled total protein content during refeeding in both control and rapamycin-injected rats. We conclude that accretion of liver protein during refeeding is dependent on mTOR-mediated activation of the translation of ribosomal proteins but not dependent on mTOR-mediated activation of cap-dependent translation initiation.
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PMID:Rapamycin inhibits liver growth during refeeding in rats via control of ribosomal protein translation but not cap-dependent translation initiation. 1636 54

BCAAs stimulate protein synthesis in in vitro preparations of skeletal muscle. Likewise, the stimulation of protein synthesis in skeletal muscle produced by intake of a mixed meal is due largely to BCAAs. Of the three BCAAs, leucine is the one primarily responsible for the stimulation of protein synthesis under these circumstances. The stimulatory effect of leucine on protein synthesis is mediated through upregulation of the initiation of mRNA translation. A number of mechanisms, including phosphorylation of ribosomal protein S6 Kinase, eukaryotic initiation factor (eIF)4E binding protein-1, and eIF4G, contribute to the effect of leucine on translation initiation. These mechanisms not only promote global translation of mRNA but also contribute to processes that mediate discrimination in the selection of mRNA for translation. A key component in a signaling pathway controlling these phosphorylation-induced mechanisms is the protein kinase, termed the mammalian target of rapamycin (mTOR). The activity of mTOR toward downstream targets is controlled in part through its interaction with the regulatory-associated protein of mTOR (known as raptor) and the G protein beta-subunit-like protein. Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain (Rheb), a GTPase that activates mTOR, and tuberin (also known as TSC2), a GTPase-activating protein, which, with its binding partner hamartin (also known as TSC1), acts to repress mTOR. Candidates for mediating the action of leucine to stimulate signaling through the mTOR pathway include TSC2, Rheb, and raptor. The current state of our understanding of how leucine acts on these signaling pathways and molecular mechanisms to stimulate protein synthesis in skeletal muscle is summarized in this article.
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PMID:Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. 1636 87

BCAAs (leucine, isoleucine, and valine), particularly leucine, have anabolic effects on protein metabolism by increasing the rate of protein synthesis and decreasing the rate of protein degradation in resting human muscle. Also, during recovery from endurance exercise, BCAAs were found to have anabolic effects in human muscle. These effects are likely to be mediated through changes in signaling pathways controlling protein synthesis. This involves phosphorylation of the mammalian target of rapamycin (mTOR) and sequential activation of 70-kD S6 protein kinase (p70 S6 kinase) and the eukaryotic initiation factor 4E-binding protein 1. Activation of p70 S6 kinase, and subsequent phopsphorylation of the ribosomal protein S6, is associated with enhanced translation of specific mRNAs. When BCAAs were supplied to subjects during and after one session of quadriceps muscle resistance exercise, an increase in mTOR, p70 S6 kinase, and S6 phosphorylation was found in the recovery period after the exercise with no effect of BCAAs on Akt or glycogen synthase kinase 3 (GSK-3) phosphorylation. Exercise without BCAA intake led to a partial phosphorylation of p70 S6 kinase without activating the enzyme, a decrease in Akt phosphorylation, and no change in GSK-3. It has previously been shown that leucine infusion increases p70 S6 kinase phosphorylation in an Akt-independent manner in resting subjects; however, a relation between mTOR and p70 S6 kinase has not been reported previously. The results suggest that BCAAs activate mTOR and p70 S6 kinase in human muscle in the recovery period after exercise and that GSK-3 is not involved in the anabolic action of BCAAs on human muscle.
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PMID:Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. 1636 96

The Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathway is considered a central regulator of protein synthesis and of cell proliferation, differentiation, and survival. However, the role of the Akt/mTOR/p70S6K pathway in lung carcinoma remains unknown. We previously showed that fibronectin, a matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates non-small cell lung carcinoma (NSCLC) cell growth and survival. Herein, we explore the role of the Akt/mTOR/p70S6K pathway in fibronectin-induced NSCLC cell growth. We found that fibronectin stimulated the phosphorylation of Akt, an upstream inducer of mTOR, and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), two downstream targets of mTOR in NSCLC cells (H1792 and H1838), whereas it inhibited the phosphatase and tensin homologue deleted on chromosome 10, a tumor suppressor protein that antagonizes the phosphatidylinositol 3-kinase/Akt signal. In addition, treatment with fibronectin inhibited the mRNA and protein expression of LKB1 as well as the phosphorylation of AMP-activated protein kinase (AMPKalpha), both known to down-regulate mTOR. Rapamycin, an inhibitor of mTOR, blocked the fibronectin-induced phosphorylation of p70S6K and 4E-BP1. Akt small interfering RNA (siRNA) and an antibody against the fibronectin-binding integrin alpha5beta1 also blocked the p70S6K phosphorylation in response to fibronectin. In contrast, an inhibitor of extracellular signal-regulated kinase 1/2 (PD98095) had no effect on fibronectin-induced phosphorylation of p70S6K. Moreover, the combination of rapamycin and siRNA for Akt blocked fibronectin-induced cell proliferation. Taken together, these observations suggest that fibronectin-induced stimulation of NSCLC cell proliferation requires activation of the Akt/mTOR/p70S6K pathway and is associated with inhibition of LKB1/AMPK signaling.
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PMID:Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. 1639 45

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