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)

Transcription factors derived from CCAAT/enhancer binding protein (C/EBP)alpha and C/EBPbeta genes control differentiation and proliferation in a number of cell types. Various C/EBP isoforms arise from unique C/EBPbeta and C/EBPalpha mRNAs by differential initiation of translation. These isoforms retain different parts of the amino terminus and therefore display different functions in gene regulation and proliferation control. We show that PKR and mTOR signaling pathways control the ratio of C/EBP isoform expression through the eukaryotic translation initiation factors eIF-2alpha and eIF-4E, respectively. An evolutionary conserved upstream open reading frame in C/EBPalpha and C/EBPbeta mRNAs is a prerequisite for regulated initiation from the different translation initiation sites and integrates translation factor activity. Deregulated translational control leading to aberrant C/EBPalpha and C/EBPbeta isoform expression or ectopic expression of truncated isoforms disrupts terminal differentiation and induces a transformed phenotype in 3T3-L1 cells. Our results demonstrate that the translational controlled ratio of C/EBPalpha and C/EBPbeta isoform expression determines cell fate.
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PMID:Translational control of C/EBPalpha and C/EBPbeta isoform expression. 1092 6

In pancreatic beta-cells, glucose causes a rapid increase in the rate of protein synthesis. However, the mechanism by which this occurs is poorly understood. In this report, we demonstrate, in the pancreatic beta-cell line MIN6, that glucose stimulates the recruitment of ribosomes onto the mRNA, indicative of an increase in the rate of the initiation step of protein synthesis. This increase in the rate of initiation is not mediated through an increase in the availability of the initiation complex eIF4F, because glucose is unable to stimulate eIF4F assembly or, in the absence of amino acids, modulate the phosphorylation status of 4E-BP1. Moreover, in MIN6 cells and isolated islets of Langerhans, rapamycin, an inhibitor of the mammalian target of rapamycin, only partially inhibited glucose-stimulated protein synthesis. However, we show that glucose stimulates the dephosphorylation of eIF2 alpha in MIN6 cells and the assembly of the translational ternary complex, eIF2-GTP.Met-tRNAi, in both MIN6 cells and islets of Langerhans. The changes in the phosphorylation of eIF2 alpha are not mediated by the PKR-like endoplasmic reticulum eIF2 alpha kinase (PERK), because PERK is not phosphorylated at low glucose concentrations and overexpression of a dominant negative form of PERK has no significant effect on either glucose-stimulated protein synthesis or the phosphorylation of eIF2 alpha. Taken together, these results indicate that glucose-stimulated protein synthesis in pancreatic beta-cells is regulated by a mechanism largely independent of the activity of mammalian target of rapamycin, but which is likely to be dependent on the availability of the translational ternary complex, regulated by the phosphorylation status of eIF2 alpha.
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PMID:Glucose-stimulated protein synthesis in pancreatic beta-cells parallels an increase in the availability of the translational ternary complex (eIF2-GTP.Met-tRNAi) and the dephosphorylation of eIF2 alpha. 1547 56

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by two major lesions: extracellular senile plaques and intraneuronal neurofibrillary tangles. beta-Amyloid (Abeta) is known to play a major role in the pathogenesis of AD. Protein synthesis and especially translation initiation are modulated by different factors, including the PKR/eIF2 and the mTOR/p70S6K pathways. mRNA translation is altered in the brain of AD patients. Very little is known about the translation control mediated by mTOR in AD, although mTOR is a central regulator of translation initiation and also ribosome biogenesis and cell growth and proliferation. In this study, by using Western blotting, we show that mTOR pathway is down-regulated by Abeta treatment in human neuroblastoma cells, and the underlying mechanism explaining a transient activation of p70S6K is linked to cross-talk between mTOR and ERK1/2 at this kinase level. This phenomenon is associated with caspase-3 activation, and inhibition of mTOR by the inhibitor rapamycin enhances Abeta-induced cell death. Moreover, in our cell model, insulin-like growth factor-1 is able to increase markedly the p70S6K phosphorylation controlled by mTOR and reduces the caspase-3 activity, but its protective effect on Abeta cell death is mediated via an mTOR-independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Abeta toxicity and could represent a possible target for modulating Abeta toxicity.
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PMID:The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide. 1695 84

Phosphoinositide-3 kinase (PI3K) plays an important role in signal transduction in response to a wide range of cellular stimuli involved in cellular processes that promote cell proliferation and survival. Phosphorylation of the alpha subunit of the eukaryotic translation initiation factor eIF2 at Ser51 takes place in response to various types of environmental stress and is essential for regulation of translation initiation. Herein, we show that a conditionally active form of the eIF2alpha kinase PKR acts upstream of PI3K and turns on the Akt/PKB-FRAP/mTOR pathway leading to S6 and 4E-BP1 phosphorylation. Also, induction of PI3K signaling antagonizes the apoptotic and protein synthesis inhibitory effects of the conditionally active PKR. Furthermore, induction of the PI3K pathway is impaired in PKR(-/-) or PERK(-/-) mouse embryonic fibroblasts (MEFs) in response to various stimuli that activate each eIF2alpha kinase. Mechanistically, PI3K signaling activation is indirect and requires the inhibition of protein synthesis by eIF2alpha phosphorylation as demonstrated by the inactivation of endogenous eIF2alpha by small interfering RNA or utilization of MEFs bearing the eIF2alpha Ser51Ala mutation. Our data reveal a novel property of eIF2alpha kinases as activators of PI3K signaling and cell survival.
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PMID:A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway. 1759 16

To investigate the mechanism by which beta-hydroxy-beta-methylbutyrate (HMB) attenuates the depression of protein synthesis in the skeletal muscle of cachectic mice, a study has been carried out in murine myotubes in the presence of proteolysis-inducing factor (PIF). PIF inhibited protein synthesis by 50% within 4 h, and this was effectively attenuated by HMB (25-50 muM). HMB (50 muM) alone stimulated protein synthesis, and this was attenuated by rapamycin (27 nM), an inhibitor of mammalian target of rapamycin (mTOR). Further evidence for an involvement of this pathway was shown by an increased phosphorylation of mTOR, the 70-kDa ribosomal S6 kinase (p70(S6k)), and initiation factor 4E-binding protein (4E-BP1) and an increased association of eukaryotic initiation factor 2 (eIF4E) with eIF4G. PIF alone induced a transient (1-2 h) stimulation of phosphorylation of mTOR and p70(S6k). However, in the presence of HMB, phosphorylation of mTOR, p70(S6k), and 4E-BP1 was increased, and inactive 4E-BP1-eIF4E complex was reduced, whereas the active eIF4G.eIF4E complex was increased, suggesting continual stimulation of protein synthesis. HMB alone reduced phosphorylation of elongation factor 2, but this effect was not seen in the presence of PIF. PIF induced autophosphorylation of the double-strand RNA-dependent protein kinase (PKR), leading to phosphorylation of eIF2 on the alpha-subunit, which would inhibit protein synthesis. However, in the presence of HMB, phosphorylation of PKR and eIF2alpha was attenuated, and this was also observed in skeletal muscle of cachectic mice administered HMB (0.25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms.
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PMID:Signaling pathways initiated by beta-hydroxy-beta-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli. 1760 54

In the present study, the BCAAs (branched-chain amino acids) leucine and valine caused a significant suppression in the loss of body weight in mice bearing a cachexia-inducing tumour (MAC16), producing a significant increase in skeletal muscle wet weight, through an increase in protein synthesis and a decrease in degradation. Leucine attenuated the increased phosphorylation of PKR (double-stranded-RNA-dependent protein kinase) and eIF2alpha (eukaryotic initiation factor 2alpha) in skeletal muscle of mice bearing the MAC16 tumour, due to an increased expression of PP1 (protein phosphatase 1). Weight loss in mice bearing the MAC16 tumour was associated with an increased amount of eIF4E bound to its binding protein 4E-BP1 (eIF4E-binding protein 1), and a progressive decrease in the active eIF4G-eIF4E complex due to hypophosphorylation of 4E-BP1. This may be due to a reduction in the phosphorylation of mTOR (mammalian target of rapamycin), which may also be responsible for the decreased phosphorylation of p70(S6k) (70 kDa ribosomal S6 kinase). There was also a 5-fold increase in the phosphorylation of eEF2 (eukaryotic elongation factor 2), which would also decrease protein synthesis through a decrease in translation elongation. Treatment with leucine increased phosphorylation of mTOR and p70(S6k), caused hyperphosphorylation of 4E-BP1, reduced the amount of 4E-BP1 associated with eIF4E and caused an increase in the eIF4G-eIF4E complex, together with a reduction in phosphorylation of eEF2. These changes would be expected to increase protein synthesis, whereas a reduction in the activation of PKR would be expected to attenuate the increased protein degradation.
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PMID:Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. 1762 10

Inhibition of double-stranded RNA-dependent protein kinase (PKR) represents an interesting strategy for neuroprotection. However, inhibiting this kinase which triggers the apoptotic process could favour in counterpart cell proliferation and tumorigenesis. Here, we use an in vivo model of 7-day-old rat displaying a high activation of brain PKR to investigate the effects of a new PKR inhibitor identified as an oxindole/imidazole derivative (C16). We show for the first time that acute systemic injection of C16 specifically inhibits the apoptotic PKR/eIF2alpha signaling pathway without stimulating the proliferative mTOR/p70S6K signaling mechanism.
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PMID:The oxindole/imidazole derivative C16 reduces in vivo brain PKR activation. 1776 Nov 71

Previous studies demonstrated that the PKR (double-stranded RNA-activated protein kinase) pathway was activated while the mTOR (mammalian target of rapamycin) pathway was inhibited in Alzheimer's disease (AD). Here, we analysed upstream and downstream factors of mTOR in brain of APP(SL)/PS1 KI mice displaying a massive neuronal loss in hippocampus. While mTOR levels were not modified, we found a great activation of Akt with a robust accumulation of P-Akt((T308)) in non-apoptotic neurons at 6 months of age. At the opposite, a significant decrease of the p70/85S6K activation was observed in brain of PS1 KI and APP(SL)/PS1 KI mice with a very weak or no nucleocytoplasmic P-p70/85S6K((T389)) staining in apoptotic neurons of APP(SL)/PS1 KI mice. Furthermore, the activation of Erk1/2, 4E-BP1 and p70S6K((T421/S424)) (substrate of Erk1/2), except eIF4E, was not modified. These findings demonstrate a clear dissociation between Akt and ribosomal S6K signaling markers in these mice which could be involved in the AD pathological process.
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PMID:Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer's disease. 1802 54

Stimulation of cholinergic muscarinic receptors has been shown to provide substantial protection from DNA damage, oxidative stress and mitochondrial impairment, insults that may be encountered by neurons in development, aging, or neurodegenerative diseases. A study recently indicated that the activation of muscarinic receptors in astrocytoma cells modified the expression of the kinase p70S6K involved in the translational control. The translational control is in part regulated by a cascade of phosphorylation affecting proteins of the anti-apoptotic way controlled by mTOR (mammalian target of rapamycin) and the pro-apoptotic way controlled by PKR. The aim of our study was to investigate the effect of cholinergic muscarinic stimulation by an agonist oxotremorine on the anti-apoptotic way of translational control, in human neuroblastoma cells and in mice brain. Our results showed that muscarinic receptor activation significantly increased the expression of phosphorylated p70S6K, eIF4E and ERK without modification of mTOR activity in neuroblastoma cells and in cerebral cortex and hippocampus of mice, suggesting a stimulation of protein synthesis. Our findings support the notion that synaptic activity, through activation of neurotransmitter receptors, can provide substantial support of cellular survival mechanisms and suggest that loss of such synaptic input increases vulnerability to insult-induced programmed cell death.
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PMID:Activation of the protein p7OS6K via ERK phosphorylation by cholinergic muscarinic receptors stimulation in human neuroblastoma cells and in mice brain. 1880 77

beta-Hydroxy-beta-methylbutyrate (HMB; 50 microM) has been shown to attenuate the depression in protein synthesis in murine myotubes in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) with or without interferon-gamma (IFN-gamma), and angiotensin II (ANG II). The mechanism for the depression of protein synthesis by all three agents was the same and was attributed to activation of double-stranded RNA-dependent protein kinase (PKR) with the subsequent phosphorylation of eukaryotic initiation factor 2 (eIF2) on the alpha-subunit as well as increased phosphorylation of the elongation factor (eEF2). Myotubes expressing a catalytically inactive PKR variant, PKRDelta6, showed no depression of protein synthesis in response to either LPS or TNF-alpha, confirming the importance of PKR in this process. There was no effect of any of the agents on phosphorylation of mammalian target of rapamycin (mTOR) or initiation factor 4E-binding protein (4E-BP1), and thus no change in the amount of eIF4E bound to 4E-BP1 or the concentration of the active eIF4E.eIF4G complex. HMB attenuated phosphorylation of eEF2, possibly by increasing phosphorylation of mTOR, and also attenuated phosphorylation of eIF2alpha by preventing activation of PKR. These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions.
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PMID:Attenuation of depression of muscle protein synthesis induced by lipopolysaccharide, tumor necrosis factor, and angiotensin II by beta-hydroxy-beta-methylbutyrate. 1885 27


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