UNIPROT:P42345 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In eukaryotic cells, amino acid depletion reduces translation by a mechanism involving phosphorylation of eukaryotic initiation factor-2 (eIF2). Herein we describe that mice lacking the eIF2 kinase, general control nonderepressible 2 (GCN2) fail to alter the phosphorylation of this initiation factor in liver, and are moribund in response to dietary leucine restriction. Wild-type (GCN2(+/+)) and two strains of GCN2 null (GCN2(-/-)) mice were provided a nutritionally complete diet or a diet devoid of leucine or glycine for 1 h or 6 days. In wild-type mice, dietary leucine restriction resulted in loss of body weight and liver mass, yet mice remained healthy. In contrast, a significant proportion of GCN2(-/-) mice died within 6 days of the leucine-deficient diet. Protein synthesis in wild-type livers was decreased concomitant with increased phosphorylation of eIF2 and decreased phosphorylation of 4E-BP1 and S6K1, translation regulators controlled nutritionally by mammalian target of rapamycin. Whereas translation in the liver was decreased independent of GCN2 activity in mice fed a leucine-free diet for 1 h, protein synthesis in GCN2(-/-) mice at day 6 was enhanced to levels measured in mice fed the complete diet. Interestingly, in addition to a block in eIF2 phosphorylation, phosphorylation of 4E-BP1 and S6K1 was not decreased in GCN2(-/-) mice deprived of leucine for 6 days. This suggests that GCN2 activity can also contribute to nutritional regulation of the mammalian target of rapamycin pathway. As a result of the absence of these translation inhibitory signals, liver weights were preserved and instead, skeletal muscle mass was reduced in GCN2(-/-) mice fed a leucine-free diet. This study indicates that loss of GCN2 eIF2 kinase activity shifts the normal maintenance of protein mass away from skeletal muscle to provide substrate for continued hepatic translation.
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PMID:Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. 1521 27

The BCAA, leucine, stimulates protein synthesis in skeletal muscle in part through enhanced initiation of mRNA translation. However, understanding how leucine regulates protein synthesis remains elusive. The intent of the present investigation was to examine the effect of leucine, independent of other regulatory agents, on key events in translation initiation in skeletal muscle and to elucidate the extent to which signaling through the mammalian target of rapamycin (mTOR) accounts for the effect of the amino acid on protein synthesis. Hindlimb preparations from postabsorptive rats were perfused with medium containing food-deprived (1X) or superphysiologic (10X) concentrations of leucine with all other amino acids at 1X concentration. Protein synthesis was significantly greater in both gastrocnemius and soleus perfused with 10X compared with 1X leucine. The stimulatory effects of leucine on protein synthesis were unaffected by a specific inhibitor of PI3-kinase (LY 294002). Moreover, signaling through mTOR, as monitored by the phosphorylation status of eukaryotic initiation factor (eIF)4E binding protein-1 (4E-BP1) or the 70-kDa ribosomal protein S6 kinase (S6K1), was not further enhanced by 10X compared with 1X leucine. However, binding of eIF4E to eIF4G and eIF4G(Ser-1108) phosphorylation in the eIF4E immunoprecipitate were enhanced as was eIF4G(Ser-1108) phosphorylation in the total tissue extract after perfusion with medium containing 10X leucine. Collectively, these observations illustrate an experimental model whereby leucine in the absence of other regulatory agents stimulates eIF4E. eIF4G assembly and protein synthesis directly in skeletal muscle, possibly by augmenting phosphorylation of eIF4G through a signaling pathway independent of mTOR.
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PMID:Leucine regulates translation initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. 1522 57

Previous studies have shown that oral administration of leucine to fasted rats results in a preferential increase in liver in the translation of mRNAs containing an oligopyrimidine sequence at the 5'-end of the message (i.e. a TOP sequence). TOP mRNAs include those encoding the ribosomal proteins (rp) and translation elongation factors. In cells in culture, the preponderance of evidence suggests that translation of TOP mRNAs is regulated by the mammalian target of rapamycin (mTOR), a protein kinase that signals through ribosomal protein S6 kinase (S6K1) to rpS6. However, the results of previous studies were recently challenged by several reports suggesting that translation of TOP mRNAs is independent of mTOR, S6K1, and S6 phosphorylation. The purpose of the present study was to evaluate the role of mTOR in the stimulation of TOP mRNA translation by leucine in vivo. Fasted rats were treated with the mTOR inhibitor, rapamycin, prior to oral administration of leucine. It was found that rapamycin severely attenuated leucine-induced signaling through mTOR in liver. In addition, rapamycin prevented the enhanced translation of TOP mRNAs in rats administered leucine, as assessed by a decrease in the proportion of TOP mRNAs associated with polysomes (i.e. those mRNAs being actively translated). Instead, in rapamycin-treated rats, ribosomal protein mRNAs accumulated in the fraction containing monosomes (mRNA bound to one ribosome). The results suggest that in liver in vivo, mTOR-dependent signaling is critical for maximal stimulation of TOP mRNA translation.
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PMID:The mTOR signaling pathway mediates control of ribosomal protein mRNA translation in rat liver. 1531 64

Age-related loss of muscle protein may involve a decreased response to anabolic factors of muscle protein synthesis through dysregulation of translation factors. To verify this hypothesis, we simultaneously investigated muscle protein synthesis and expression of some factors implicated in insulin signal transduction during hyperinsulinemia and hyperaminoacidemia in 6 young (25+/-1 year; mean+/-sem) and 8 elderly subjects (72+/-2 year). Incorporation of L-[1-13C] leucine in muscle proteins (fractional synthesis rate, FSR) was measured in vastus lateralis, before and during a euglycemic hyperinsulinemic hyperaminoacidemic clamp, together with Western blot analysis of protein kinase B (PKB), mTOR, 4E-BP1, and S6K1 phosphorylation. In basal state, muscle protein FSR was reduced in elderly in comparison with young subjects (0.061+/-0.004% per hour) vs 0.082+/-0.010% per hour, elderly vs. young, P<0.05). During clamp, muscle protein FSR was stimulated in young (0.119+/-0.006% per hour; P<0.05), but this response was significantly lower in elderly subjects (0.084+/-0.005% per hour, P<0.05 vs young subjects). Phosphorylation of PKB, mTOR, and 4E-BP1 were similarly increased by insulin and amino acid in both groups, except for S6K1 phosphorylation, which was not stimulated in elderly subjects. In conclusion, 1) response of muscle protein synthesis to insulin and amino acid is impaired in elderly humans; 2) a defect in S6K1 pathway activation may be responsible for this alteration. This modification is a mechanistic basis of sarcopenia development during aging.
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PMID:Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. 1531 61

Leucine (Leu) is known to stimulate translation initiation of protein synthesis at mammalian target of rapamycin (mTOR) in the insulin signaling pathway. However, potential feedback from mTOR to upstream aspects of the insulin signaling pathway remains controversial. This study evaluates the impact of a physiological oral dose of Leu and/or carbohydrate (CHO) on upstream elements of the insulin signaling pathway using phosphatidylinositol 3-kinase (PI 3-kinase) activity and glucose uptake as markers for insulin sensitivity and glucose homeostasis. Rats (approximately 200 g) were fasted 12 h and administered oral doses of CHO (1.31 g glucose, 1.31 g sucrose), Leu (270 mg), or CHO plus Leu. Animals were killed at 15, 30, 60, and 90 min after treatment. Plasma and gastrocnemius muscles were collected for analyses. Treatments were designed to produce elevated blood glucose and insulin with basal levels of Leu (CHO); elevated Leu with basal levels of glucose and insulin (Leu); or a combined increase of glucose, insulin, and Leu (CHO + Leu). The CHO treatment stimulated PI 3-kinase activity and glucose uptake with no effect on the downstream translation initiation factor eIF4E. Leu alone stimulated the release of the translation initiation factor eIF4E from 4E-BP1 with no effects on PI 3-kinase activity or glucose uptake. The CHO + Leu treatment reduced the magnitude and duration of the PI 3-kinase response but maintained glucose uptake similar to the CHO treatment and eIF4E levels similar to the Leu treatment. These findings demonstrate that Leu reduces insulin-stimulated PI 3-kinase activity while increasing downstream translation initiation and with no effect on net glucose transport in skeletal muscle.
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PMID:Leucine reduces the duration of insulin-induced PI 3-kinase activity in rat skeletal muscle. 1533 47

Myocardial dysfunction is a common manifestation of thermal injury, the etiology of which appears to be multifactorial. We have previously demonstrated that burn injury impairs cardiac protein synthesis at the level of translation initiation. The purpose of the present study was to determine whether oral administration of leucine, which is known to stimulate translation initiation in skeletal muscle, can ameliorate burn-induced changes in signal transduction pathways known to regulate protein synthesis in cardiac muscle. To address this aim, thermal injury was produced by a 40% total body surface area full-thickness scald burn in anesthetized rats, and the animals were studied in the fasted condition 24 h later; appropriate time-matched nonburned control rats were also included. Separate groups of control and burn rats also received an oral gavage of leucine. To identify potential mechanisms responsible for regulating mRNA translation in cardiac muscle, several eukaryotic initiation factors (eIFs) were examined using immunoprecipitation and immunoblotting techniques. Hearts from burned rats demonstrated a redistribution of eIF4E as evidenced by the increased binding of the translational repressor 4E-BP1 with eIF4E, a decreased amount of eIF4E bound with eIF4G, and a decreased amount of the hyperphosphorylated gamma-isoform of 4E-BP1. Furthermore, constitutive phosphorylation of mTOR, the ribosomal protein S6, and eIF4G was also decreased in hearts from burned rats. In control rats, leucine failed to alter eIF4E distribution but did increase the phosphorylation of S6K1 and S6. However, in hearts from burn rats, leucine acutely reversed the alterations in eIF4E distribution as well as the changes in S6, eIF4G, and mTOR phosphorylation. These data suggest that oral administration of leucine can acutely reverse multiple defects in cardiac translation initiation produced by thermal injury.
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PMID:Leucine acutely reverses burn-induced alterations in translation initiation in heart. 1537 87

Endotoxin (i.e., lipopolysaccharide, LPS) impairs skeletal muscle protein synthesis. Although this impairment is not acutely associated with a decreased plasma concentration of total amino acids, LPS may blunt the anabolic response to amino acids. To examine this hypothesis, rats were injected intraperitoneally with LPS or saline (Sal) and 4 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess signaling components important in the translational control of protein synthesis. In the Sal-Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated control rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E x 4E-BP1 complex to the active eIF4E x eIF4G complex. In LPS-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were partially or completely abrogated. LPS also antagonized the Leu-induced increase in phosphorylation of S6K1, ribosomal protein S6 and mTOR. Neither LPS nor leu altered the total amount or phosphorylation of TSC2 in muscle. The ability of LPS to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin or Leu between groups. Furthermore, the replacement of plasma insulin-like growth factor (IGF)-I in LPS-treated rats to basal levels also did not ameliorate the defect in leucine-induced phosphorylation of S6K1 or S6, although it did reverse the LPS-induced decrease in the constitutive phosphorylation of mTOR, S6 and 4E-BP1. Pretreatment with the glucocorticoid receptor antagonist RU486 was unable to prevent the LPS-induced leucine resistance. In contrast, to the abovementioned results with leucine, LPS did not prevent the ability of pharmacological levels of IGF-I to phosphorylate 4E-BP1, S6K1, mTOR or alter the availability of eIF4E. Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation initiation and protein synthesis.
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PMID:Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. 1538 31

Amino acids are nutrients responsible for mammalian target of rapamycin (mTOR) regulation in mammalian cells. The mTOR protein is mainly known for its role in regulating cell growth, notably via protein synthesis. In addition to amino acids, mTOR is regulated by insulin via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. mTOR mediates crosstalk between amino acids and insulin signaling. We show that in freshly isolated rat adipocytes, insulin stimulates the phosphorylation of mTOR on serine 2448, a protein kinase B (PKB) consensus phosphorylation site. This site is also phosphorylated by amino acids, which in contrast to insulin do not activate PKB. Moreover, insulin and amino acids have an additive effect on mTOR phosphorylation, indicating that they act via two independent pathways. Importantly, amino acids, notably leucine, permit insulin to stimulate PKB when PI 3-kinase is inhibited. They also rescue glucose transport and the mTOR pathway. Further, leucine alone can improve insulin activation of PKB in db/db mice. Our results define the importance of amino acids in insulin signaling and reveal leucine as a key amino acid in disease situations associated with insulin-resistance in adipocytes.
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PMID:Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. 1547 67

Decreased translation initiation adversely impacts protein synthesis and contributes to the myocardial dysfunction produced by sepsis. Therefore, the purpose of the present study was to identify sepsis-induced changes in signal transduction pathways known to regulate translation initiation in cardiac muscle and to determine whether the stimulatory effects of leucine can reverse the observed defects. To address this aim, sepsis was produced by cecal ligation and puncture (CLP) in anesthetized rats and the animals studied in the fasted condition 24 h later. Separate groups of septic and time-matched control rats also received an oral gavage of leucine. To identify potential mechanisms responsible for regulating cap-dependent mRNA translation in cardiac muscle, several eukaryotic initiation factors (eIFs) were examined. Under basal conditions, hearts from septic rats demonstrated a redistribution of the rate-limiting factor eIF4E due to increased binding of the translational repressor 4E-BP1 with eIF4E. However, this change was independent of an alteration in the phosphorylation state of 4E-BP1. The phosphorylation of mTOR, S6K1, the ribosomal protein (rp) S6, and eIF4G was not altered in hearts from septic rats under basal conditions. In control rats, leucine failed to alter eIF4E distribution but increased the phosphorylation of S6K1 and S6. In contrast, in hearts from septic rats leucine acutely reversed the alterations in eIF4E distribution. However, the ability of leucine to increase S6K1 and rpS6 phosphorylation in septic hearts was blunted. Sepsis increased the content of tumor necrosis factor (TNF)-alpha in heart and pre-treatment of rats with a TNF antagonist prevented the above-mentioned sepsis-induced changes. These data indicate that oral administration of leucine acutely reverses sepsis-induced alterations eIF4E distribution observed under basal conditions but the anabolic actions of this amino acid on S6K1 and rpS6 phosphorylation remain blunted, providing evidence for a leucine resistance. Finally, TNFalpha, either directly or indirectly, appears to mediate the sepsis-induced defects in myocardial translation initiation.
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PMID:TNFalpha mediates sepsis-induced impairment of basal and leucine-stimulated signaling via S6K1 and eIF4E in cardiac muscle. 1553 70

Amino acids, especially branched-chain amino acids such as l-leucine, have been shown to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through the mTOR signaling pathway. In our recent study, l-arginine was also shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. l-Glutamine is an amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells. In this study, we showed that l-glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Although the molecular mechanism of l-glutamine-induced inhibition of the mTOR signaling pathway is still unknown, the presence of this novel signal pathway may indicate that individual amino acids play specific roles for cellular proliferation and growth.
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PMID:Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells. 1556 68

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