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 mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on S1P-induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40 microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is known to mobilize intracellular calcium in fibroblasts, had no effect alone, but it approximately doubled the combined stimulatory effects of ethanol and S1P on DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor 4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined, ethanol detectably enhanced the stimulatory effects of S1P on the phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP) kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for 10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1 kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P-induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6 kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the c-Raf-1/MAP kinase-dependent growth regulatory pathways.
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PMID:Ethanol potentiates the mitogenic effects of sphingosine 1-phosphate by a zinc- and calcium-dependent mechanism in fibroblasts. 1033 73

Heart disease represents an important etiology of mortality in chronic alcoholics. The purpose of the present study was to examine potential mechanisms for the inhibitory effect of chronic alcohol exposure (16 wk) on the regulation of myocardial protein metabolism. Chronic alcohol feeding resulted in a lower heart weight and 25% loss of cardiac protein per heart compared with pair-fed controls. The loss of protein mass resulted in part from a diminished (30%) rate of protein synthesis. Ethanol exerted its inhibition of protein synthesis through diminished translational efficiency rather than lower RNA content. Chronic ethanol administration decreased the abundance of eukaryotic initiation factor (eIF)4G associated with eIF4E in the myocardium by 36% and increased the abundance of the translation response protein (4E-BP1) associated with eIF4E. In addition, chronic alcohol feeding significantly reduced the extent of p70S6 kinase (p70(S6K)) phosphorylation. The decreases in the phosphorylation of 4E-BP1 and p70(S6K) did not result from a reduced abundance of mammalian target of rapamycin (mTOR). These data suggest that a chronic alcohol-induced impairment in myocardial protein synthesis results in part from inhibition in peptide chain initiation secondary to marked changes in eIF4E availability and p70(S6K) phosphorylation.
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PMID:Effects of chronic alcohol consumption on regulation of myocardial protein synthesis. 1151 93

Acute alcohol (EtOH) intoxication impairs skeletal muscle protein synthesis. Although this impairment is not associated with a decrease in the total plasma amino acid concentration, EtOH may blunt the anabolic response to amino acids. To examine this hypothesis, rats were administered EtOH or saline (Sal) and 2.5 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in translational control of protein synthesis. Oral Leu increased muscle protein synthesis by the same magnitude in Sal- and EtOH-treated rats. However, the increase in the latter group was insufficient to overcome the suppressive effect of EtOH, and the rate of synthesis remained lower than that observed in rats from the Sal-Sal group. Leu markedly increased phosphorylation of Thr residues 36, 47, and 70 on 4E-binding protein (BP)1 in muscle from rats not receiving EtOH, and this response was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E. 4E-BP1 to the active eIF4E. eIF4G complex. In EtOH-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E availability were partially abrogated. EtOH also prevented the Leu-induced increase in phosphorylation of eIF4G, the serine/threonine protein kinase S6K1, and the ribosomal protein S6. Moreover, EtOH attenuated the Leu-induced phosphorylation of the mammalian target of rapamycin (mTOR). The ability of EtOH to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor I, or Leu. Finally, although EtOH increased the plasma corticosterone concentration, inhibition of glucocorticoid action by RU-486 was unable to prevent EtOH-induced defects in the ability of Leu to stimulate 4E-BP1, S6K1, and mTOR phosphorylation. Hence, ethanol produces a leucine resistance in skeletal muscle, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR, that is independent of elevations in endogenous glucocorticoids.
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PMID:Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle. 1294 22

Acute alcohol intoxication impairs myocardial protein synthesis in rats, secondary to a diminished mRNA translational efficiency. Decreased mRNA translational efficiency occurs through altered regulation of peptide chain initiation. The purpose of the present set of experiments was to determine whether acute alcohol intoxication alters the phosphorylation state of eukaryotic initiation factor (eIF) 4G, eIF4G.eIF4E complex formation, and the mammalian target of rapamycin (mTOR) signaling pathway in the heart. Acute alcohol intoxication was induced by injection of alcohol (75 mmol/kg body wt ip). Control animals received an equal volume of saline. Alcohol administration enhanced phosphorylation of eIF4G (Ser(1108)) approximately threefold. Alcohol administration lowered formation of the active eIF4G.eIF4E complex by >90%, whereas it increased the abundance of the inactive 4E-binding protein 1 (4E-BP1).eIF4E complex by approximately 160%. Phosphorylation of mTOR on Ser(2448) and Ser(2481) was decreased by 50%. Reduced mTOR phosphorylation did not result from decreased phosphorylation of PKB. Phosphorylation of 4E-BP1 and S6 kinase 1 (Thr(389)), downstream targets of mTOR, were also reduced after acute alcohol administration. These data suggest that acute alcohol-induced impairments in myocardial mRNA translation initiation result, in part, from marked decreases in eIF4G.eIF4E complex formation, which appear to be independent of changes in phosphorylation of eIF4G but dependent on mTOR.
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PMID:Acute alcohol intoxication enhances myocardial eIF4G phosphorylation despite reducing mTOR signaling. 1538 9

Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation.
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PMID:Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. 1696

Ethanol decreases protein synthesis in cells, although the underlying regulatory mechanisms of this process are not fully established. In the present study incubation of C2C12 myocytes with 100 mm EtOH decreased protein synthesis while markedly increasing the phosphorylation of eukaryotic elongation factor 2 (eEF2), a key component of the translation machinery. Both mTOR and MEK pathways were found to play a role in regulating the effect of EtOH on eEF2 phosphorylation. Rapamycin, an inhibitor of mammalian target of rapamycin, and the MEK inhibitor PD98059 blocked the EtOH-induced phosphorylation of eEF2, whereas the p38 MAPK inhibitor SB202190 had no effect. Unexpectedly, EtOH decreased the phosphorylation and activity of the eEF2 upstream regulator eEF2 kinase. Likewise, treatment of cells with the inhibitor rottlerin did not block the stimulatory effect of EtOH on eEF2, suggesting that eEF2 kinase (eEF2K) does not play a role in regulating eEF2. In contrast, increased eEF2 phosphorylation was correlated with an increase in AMP-activated protein kinase (AMPK) phosphorylation and activity. Compound C, an inhibitor of AMPK, suppressed the effects of EtOH on eEF2 phosphorylation but had no effect on eEF2K, indicating that AMPK regulates eEF2 independent of eEF2K. Finally, EtOH decreased protein phosphatase 2A activity when either eEF2 or AMPK was used as the substrate. Thus, this later action may partially account for the increased phosphorylation of eEF2 in response to EtOH and the observed sensitivity of AMPK to rapamycin and PD98059 treatments. Collectively, the induction of eEF2 phosphorylation by EtOH is controlled by an increase in AMPK and a decrease in protein phosphatase 2A activity.
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PMID:Alcohol regulates eukaryotic elongation factor 2 phosphorylation via an AMP-activated protein kinase-dependent mechanism in C2C12 skeletal myocytes. 1716 44

The transient receptor potential vanilloid 1 or TRPV1 is a calcium-permeable ion channel that is activated by capsaicin, the active component of hot chilli peppers, and is involved in the development of inflammatory and neuropathic hyperalgesias. Ethanol can sensitise TRPV1-mediated responses, but the pathways contributing to the potentiation of TRPV1 by ethanol have not been clearly defined. Since the mu opioid receptor (MOP) agonist morphine can inhibit TRPV1 responses potentiated by cAMP-dependent protein kinase A (PKA), and ethanol-mediated modulation of other ion channels involves activation of PKA, we aimed to assess the contribution of MOP-sensitive pathways to the potentiation of TRPV1-mediated capsaicin responses by ethanol. Calcium responses elicited by the TRPV1 agonist capsaicin were potentiated by treatment with ethanol, but morphine was not able to inhibit ethanol-sensitised capsaicin responses. Indeed, cAMP-dependent PKA did not appear to contribute to potentiation of TRPV1 responses by ethanol, as the PKA inhibitor Rp-cAMPS did not inhibit ethanol-potentiated capsaicin responses. Similarly, treatment with specific PKC and PI3K inhibitors did not affect capsaicin responses in the presence of ethanol. However, treatment with wortmannin at concentrations reported to cause PIP2 depletion limited the ability of ethanol to sensitise TRPV1-mediated capsaicin responses. Among other plausible mechanisms, such as non-specific inhibition of kinases including mTOR, DNA-PK, MLCK, MAPK and polo-like kinases, this suggests that ethanol may affect the PIP2-TRPV1 interaction. This was confirmed by inhibition of ethanol-potentiation by the PLC inhibitor U73122. The results presented here suggest that morphine may be of limited use in inhibiting nociceptive TRPV1 responses that have been sensitised by exposure to ethanol.
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PMID:Mechanisms involved in potentiation of transient receptor potential vanilloid 1 responses by ethanol. 1782

Caveolin-1 (Cav-1) is a major structural protein of caveolae and plays an important role as a negative regulator of various signaling pathways such as the transforming growth factor-beta (TGF-beta)/smad pathway. In this study, we investigated the role of cav-1 on basal and TGF-beta1-induced expression of type I procollagen in human dermal fibroblasts. Our results demonstrated that basal and TGF-beta1-induced expression of type I procollagen were significantly increased by adenoviral cav-1 (Ad-cav-1) overexpression, while the basal level of type I procollagen was decreased by cav-1 siRNA. Overexpression of cav-1 inhibited TGF-beta1-induced phosphorylation of smad3 and transcription of 3TP-Lux and SBE luciferase reporters, suggesting that cav-1 may inhibit the TGF-beta1/smad signaling pathway. We observed that TGF-beta1-induced type I procollagen expression was decreased by smad3 siRNA transfection. However, the reduction of TGF-beta1-induced type I procollagen expression by smad3 siRNA was reversed by cav-1 overexpression. In addition, our results also showed that TGF-beta1 treatment increased the phosphorylation of Akt, and Ad-cav-1 infection augmented this TGF-beta1-induced phosphorylation of Akt. Ad-myr-Akt infection significantly increased the basal expression of type I procollagen. In contrast, TGF-beta1-induced type I procollagen expression was decreased by Akt siRNA transfection and the PI3-kinase inhibitor, LY294002, inhibited the TGF-beta1-induced type I procollagen expression and also inhibited the cav-1-induced expression of type I procollagen. In conclusion, our results suggest that cav-1 increases the basal and TGF-beta1-induced expression of type I procollagen by regulating two opposite signaling pathways: inhibiting TGF-beta1/smad signaling and activating a PI-3 kinase/Akt/mTOR-dependent pathway in human dermal fibroblasts, ultimately resulting in increased type I procollagen expression.
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PMID:Caveolin-1 increases basal and TGF-beta1-induced expression of type I procollagen through PI-3 kinase/Akt/mTOR pathway in human dermal fibroblasts. 1843 90

The most serious complication of peritoneal dialysis is encapsulating peritoneal sclerosis (EPS). The prolonged inflammatory stimuli, fibrogenic cytokine overexpression, and angiogenesis that underlie EPS ultimately result in increased production of fibrous tissue, encapsulating the bowel loops. In recent years, inhibitors of mammalian target of rapamycin (mTOR) as an alternative agent for calcineurin inhibitor toxicity have been widely used in organ transplantation. These agents have also been used since the 1990s in endovascular medicine for drug-eluting stents because of antiproliferative effects on vascular smooth muscle cells and potent anti-inflammatory properties by direct action on human immune cells. Because of the shared characteristics of EPS and other fibrotic processes, we hypothesized that everolimus, an mTOR inhibitor can reverse the process responsible for the eventual development of EPS. We allocated 32 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 - 3), plus peritoneal rest (weeks 3 - 6); and Evo-R, CG (weeks 0 - 3), plus 0.3 mg/L everolimus in drinking water (weeks 3 - 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/P urea), dialysate white blood cell count, ultrafiltration (UF) volume, and morphologic change in the parietal peritoneum. Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume, p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness, p < 0.05). Peritoneal rest has some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However; everolimus was more effective than peritoneal rest with regard to vascularity and peritoneal thickness (p < 0.05). Everolimus has beneficial effects on UF failure, inflammation, and fibrosis. Everolimus may have therapeutic value in the management of EPS.
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PMID:Effects of everolimus as an antiproliferative agent on regression of encapsulating peritoneal sclerosis in a rat model. 1898 12

Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low-dose chronic exposure to ethanol inhibits mammalian target of rapamycin (mTOR) C1 complex formation, resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global cap-dependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. Our data support a paradigm in which chronic ethanol exposure inhibits mTOR signaling in lymphocytes with a significant repression of cap-dependent translation, reducing the tumorigenic capacity of non-Hodgkin lymphoma in a human xenograft model. The ethanol-mediated repression of mTOR signaling coupled with decreased in vivo lymphoma growth underscore the critical role of mTOR signaling and translation in lymphoma.
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PMID:Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction. 1929 24


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