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)

The role of the AMP-activated kinase (AMPK) as a metabolic sensor in skeletal muscle has been far better characterized for glucose and fat metabolism than for protein metabolism. Therefore, the studies presented here were designed to examine the effects of 5-aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR)-induced AMPK signaling on effector mechanisms of mRNA translation and protein synthesis in cultures of C(2)C(12) myotubes. The findings show that, following AICAR (2 mM) treatment, AMPK phosphorylation was increased within 15 min and remained elevated throughout a 60-min time course. In association with the increase in AMPK phosphorylation, global rates of protein synthesis declined to 90, 70, and 63% of the control values at the 15-, 30-, and 60-min time points, respectively. By 60 min, polysomes disaggregated into free ribosomal subunits, suggesting an inhibition of initiation of mRNA translation. However, phosphorylation of eukaryotic elongation factor 2 was increased at 15 and 30 min but then declined to control values by 60 min, suggesting a transient inhibition of translation elongation. The decline in protein synthesis and changes in mRNA translation were associated with a repression of the mammalian target of rapamycin (mTOR) signaling pathway, as indicated by increased association of Hamartin with Tuberin, increased association of regulatory associated protein of mTOR with mTOR, and dephosphorylation of the downstream targets ribosomal protein S6 kinase-1 and eukaryotic initiation factor 4E-binding protein-1. They were also associated with activation of the MAPK signaling pathway, as indicated by increased phosphorylation of MEK1/2 and ERK1/2 and the downstream target eIF4E. Overall, the data support the conclusion that AICAR-induced AMPK activation suppresses protein synthesis through concurrent repression of mTOR signaling and activation of MAPK signaling, the combination of which modulates transient changes in the initiation and elongation phases of mRNA translation.
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PMID:Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR. 1676 Mar 36

Feeding stimulates pancreatic digestive enzyme synthesis at the translational level, and this is thought to be mediated by hormones and neurotransmitters. However, BCAAs, particularly leucine, stimulate protein synthesis in several tissues. We investigated whether BCAA stimulated the translational machinery in murine pancreas and whether their effects were independent of hormones. Rats and mice were administered (i.g. gavage) individual BCAA at 1.35 mg/g (body weight) and rat isolated pancreatic acini were incubated with BCAA under different conditions. Activation of translation initiation factors and total protein synthesis were analyzed. BCAA gavage stimulated the phosphorylation of the initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase (S6K), with leucine being the most effective. Leucine also increased the association of the initiation factors eIF4E and eIF4G, but did not affect the activity of the guanine nucleotide exchange factor eIF2B, nor total protein synthesis. BCAA acted independently of insulin signaling on isolated pancreatic acini from diabetic rats. The ability of leucine to promote phosphorylation of 4E-BP1 and S6K as well as enhance the assembly of the eIF4F complex was unimpaired in CCK-deficient mice. Finally, rapamycin (0.75 mg/kg) administered to rats 2 h before leucine gavage inhibited the phosphorylation of S6 and 4E-BP1 induced by leucine. We conclude that leucine may participate, as a signal as well as a substrate, in activating the translational machinery in pancreatic acinar cells independently of hormonal effects and that this action is through the mTOR pathway.
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PMID:Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin. 1677 39

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G(1)-S-phase regulators, including the cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL.
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PMID:Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. 1681 31

The aim of this study was to compare the training stimuli of eccentric (lengthening) and concentric (shortening) contractions regarding the effect on signaling enzymes involved in protein synthesis. Ten male subjects performed 4 x 6 maximal eccentric contractions on one leg followed by 4 x 6 maximal concentric contractions on the other. Six additional subjects performed the same protocol, but with maximal concentric and submaximal eccentric exercise of equal force to that of the maximal concentric contractions. Muscle biopsy samples were taken from the vastus lateralis before, immediately after, and 1 and 2 h after exercise in both legs. The average peak force produced during the maximal eccentric exercise was 31% higher than during the maximal concentric exercise, 2,490 (+/-100) vs. 1,894 (+/-108) N (P < 0.05). The maximal eccentric contractions led to two- to eightfold increases in the phosphorylation of p70 S6 kinase (p70(S6k)) and the ribosomal protein S6 that persisted for 2 h into recovery but no significant changes in phosphorylation of Akt or mammalian target of rapamycin (mTOR). Maximal concentric and submaximal eccentric contractions did not induce any significant changes in Akt, mTOR, p70(S6k), or S6 phosphorylation up to 2 h after the exercise. The results indicate that one session of maximal eccentric contractions activates p70(S6k) in human muscle via an Akt-independent pathway and suggest that maximal eccentric contractions are more effective than maximal concentric contractions in stimulating protein synthesis in the absence of a nutritional intake, an effect that may be mediated through a combination of greater tension and stretching of the muscle.
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PMID:Maximal lengthening contractions increase p70 S6 kinase phosphorylation in human skeletal muscle in the absence of nutritional supply. 1683 2

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.
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PMID:PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. 1691 81

Feeding promotes protein synthesis in cardiac muscle through a stimulation of the mRNA translation initiation phase of protein synthesis either secondary to nutrient-induced rises in insulin or because of direct effects of nutrients themselves. The present set of experiments establishes the effects of meal feeding on the potential signal transduction pathways that may be important in accelerating mRNA translation initiation. Hearts were obtained from male Sprague Dawley rats that had been trained to consume a meal consisting of nonpurified diet prior to, during, and following the test meal. Meal feeding raised the extent of phosphorylation of eukaryotic initiation factor (eIF)4G (Ser(1108)), which returned to basal levels within 3 h of removal of food. Likewise, meal feeding was associated with an increase in phosphorylation of eIF4E binding protein-1(4EBP1) in the gamma-form during feeding. Phosphorylation of mammalian target of rapamycin (mTOR) on Ser(2448) or Ser(2481) or 70-kDa ribosomal protein S6 kinase (S6K1) on Thr(389) was not affected by meal feeding or following removal of food. Likewise, the extent of phosphorylation of TSC2, a potential upstream regulator of mTOR, was not significantly altered during meal feeding. Phosphorylation of protein kinase B (PKB) (Thr(308)) was elevated at all time points after initiating meal feeding. Similarly, the phosphorylation of protein kinase C(PKC)-epsilon but not PKC-delta was elevated at all time points after initiating meal feeding. We conclude from these studies that meal feeding stimulates at least 2 signal pathways in cardiac muscle that raises phosphorylation of eIF4G and 4EBP1 during meal feeding and results in sustained increases in phosphorylation of PKB and PKC-epsilon.
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PMID:Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts. 1692 Aug 42

In response to traumatic brain injury (TBI), neurons initiate neuroplastic processes through the activation of intracellular signaling pathways. However, the molecular mechanisms underlying neuroplasticity after TBI are poorly understood. To study this, we utilized the fluid-percussion brain injury (FPI) model to investigate alterations in the mammalian target of rapamycin (mTOR) signaling pathways in response to TBI. Mammalian target of rapamycin stimulates mRNA translation through phosphorylation of eukaryotic initiation factor 4E binding protein-1 (4E-BP1), p70 ribosomal S6 kinase (p70S6K), and ribosomal protein S6 (rpS6). These pathways coordinate cell growth and neuroplasticity via dendritic protein synthesis. Rats received sham surgery or moderate parasagittal FPI on the right side of the parietal cortex, followed by 15 mins, 30 mins, 4 h, 24 h, or 72 h of recovery. Using Western blot analysis, we found that mTOR, p70S6K, rpS6, and 4E-BP1 phosphorylation levels were significantly increased in the ipsilateral parietal cortex and hippocampus from 30 mins to 24 h after TBI, whereas total protein levels were unchanged. Using confocal microscopy to localize these changes, we found that rpS6 phosphorylation was increased in the parietal cortex and all subregions of the hippocampus. In accordance with these results, eIF4E, a key, rate-limiting mRNA translation factor, was also phosphorylated by mitogen-activated protein kinase-interacting kinase 1 (Mnk1) 15 mins after TBI. Together, these results suggest that changes in mRNA translation may be one mechanism that neurons use to respond to trauma and may contribute to the neuroplastic changes observed after TBI.
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PMID:Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. 1695 78

Inhibitors of the mammalian target of rapamycin (mTOR) are currently in clinical trials for the treatment of breast cancer. The mechanisms through which mTOR are activated in breast cancer and the relationship of mTOR activation to steroid hormones, such as estrogen, that are known to influence breast cancer pathogenesis, are not yet understood. Using MCF-7 cells as a model, we found that 17-beta estradiol (E(2)) rapidly increased the phosphorylation of downstream targets of mTOR: p70 ribosomal protein S6 kinase, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 1. The phosphoinositide-3-kinase inhibitor, wortmannin, and the mTOR inhibitor, rapamycin, blocked E(2)-induced activation of p70 ribosomal protein S6 kinase. We hypothesized that tuberin and the small GTPase Ras homologue enriched in brain (Rheb), regulators of the mTOR pathway, mediate E(2)-induced activation of mTOR. Consistent with this hypothesis, E(2) rapidly (within 5 minutes) stimulated tuberin phosphorylation at T1462, a site at which Akt phosphorylates and inactivates tuberin. E(2) also rapidly decreased the inactive, GDP-bound form of Rheb. Finally, we found that small interfering RNA down-regulation of endogenous Rheb blocked the E(2)-stimulated proliferation of MCF-7 cells, demonstrating that Rheb is a key determinant of E(2)-dependent cell growth. Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a critical role in the regulation of E(2)-induced proliferation, and highlight Rheb as a novel molecular target for breast cancer therapy.
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PMID:Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. 1701 1

There is currently a high level of interest in signalling through the mammalian target of rapamycin (mTOR). This reflects both its key role in many cell functions and its involvement in disease states such as cancers. The best understood targets for mTOR signalling are proteins involved in controlling the translational machinery, including the ribosomal protein S6 kinases and proteins that regulate the initiation and elongation phases of translation. Indeed, there is compelling evidence that at least one of these targets of mTOR (eukaryotic initiation factor eIF4E) plays a key role in tumorigenesis. It is regulated through the mTOR-dependent phosphorylation of inhibitory proteins such as eIF4E-binding protein 1. Thus, targeting mTOR signalling may be an effective anticancer strategy, in at least a significant subset of tumours. Not all effects of mTOR are sensitive to the classical anti-mTOR drug rapamycin, and this compound also interferes with other processes besides eIF4E function. Developing new approaches to targeting mTOR for cancer therapy requires more detailed knowledge of signalling downstream of mTOR. Such advances are likely to come from further work to understand the regulation of mTOR targets such as components of the translational apparatus.
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PMID:When translation meets transformation: the mTOR story. 1704 27

Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption produce changes in hepatic drug metabolizing enzyme gene and protein expression. This difference in expression alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants and therapeutic agents, potentially impacting the efficacy and safety of therapeutic agents, and/or resulting in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone- and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory has reported that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450 (CYP), glutathione S-transferases (GST) and microsomal epoxide hydrolase (mEH), through receptors which are members of the large receptor tyrosine kinase (RTK) family, and by downstream effectors such as phosphatidylinositol 3-kinase, mitogen activated protein kinase (MAPK), Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR), and the p70 ribosomal protein S6 kinase (p70S6 kinase). Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how disease affects these signaling pathways, components, and ultimately gene expression and translational control.
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PMID:The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. 1709 48


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