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)

Cadmium (Cd) may be accumulated in human body through long-term exposure to Cd-polluted environment, resulting in neurodegeneration and other diseases. To study the mechanism of Cd-induced neurodegeneration, PC12 and SH-SY5Y cells were exposed to Cd. We observed that Cd-induced apoptosis in the cells in a time- and concentration-dependent manner. Cd rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2 and JNK, but not p38, partially protected the cells from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or down-regulation of Erk1/2, but not p38 MAPK, partially prevented Cd-induced apoptosis. To our surprise, Cd also activated mammalian target of rapamycin (mTOR)-mediated signaling pathways. Treatment with rapamycin, an mTOR inhibitor, blocked Cd-induced phosphorylation of S6K1 and eukaryotic initiation factor 4E binding protein 1, and markedly inhibited Cd-induced apoptosis. Down-regulation of mTOR by RNA interference also in part, rescued cells from Cd-induced death. These findings indicate that activation of the signaling network of MAPK and mTOR is associated with Cd-induced neuronal apoptosis. Our results strongly suggest that inhibitors of MAPK and mTOR may have a potential for prevention of Cd-induced neurodegeneration.
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PMID:MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. 1802 Dec 93

Human embryonic stem (hES) cells hold great promise for use in regenerative medicine. However, technologies first need to be established to maintain hES cells efficiently in vitro. Understanding the signaling networks involved in hES cell maintenance will prove to be essential to the development of such culture systems. Previously, we described a serum-free medium capable of supporting prolonged hES cell maintenance using sphingosine-1-phosphate (S1P) and platelet-derived growth factor (PDGF). Here, we describe an anti-apoptotic effect of S1P and PDGF in hES cells and demonstrate a direct effect of S1P in preventing hES cell apoptosis. Western blot analysis shows that S1P stimulates the phosphorylation of the mitogen-activated protein (MAP) kinases Erk1/2 but not of Akt, whereas PDGF stimulates both Erk1/2 and Akt phosphorylation. Moreover, our study suggests that the Erk1/2 and PI3K/Akt signaling pathways act independently of each other. Furthermore, neither S1P nor PDGF modify intracellular calcium concentration ([Ca(2+)]( i )) and Smad2 phosphorylation. Using pharmacological inhibitors of Erk1/2 and PI3K, our results demonstrate a critical role of the Erk1/2 and PI3K/Akt signaling pathways in mediating the anti-apoptotic effect of S1P and PDGF on hES cells. However, inhibition of the mammalian target of rapamycin (mTOR), a common downstream effector of Erk1/2 and PI3K/Akt, has no effect on hES cell apoptosis.
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PMID:Anti-apoptotic effect of sphingosine-1-phosphate and platelet-derived growth factor in human embryonic stem cells. 1804 16

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 40% within 24 h and was associated with a decreased polysome/monosome ratio that is indicative of reduced protein translation efficiency. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models had sustained tumor regressions and minimal toxicity. These data (a) provide evidence that both pathways converge on factors that regulate translation initiation and (b) support therapeutic strategies in lung cancer that simultaneously suppress the RAS and AKT signaling network.
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PMID:Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. 1805 56

The mTORC1 complex (mammalian target of rapamycin (mTOR)-raptor) is modulated by mitogen-activated protein (p44/42 MAP) kinases (p44/42) through phosphorylation and inactivation of the tuberous sclerosis complex. However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported. We show that in two cancer cell lines regulation of the p44/42 MAPKs is mTORC1-dependent. In Rh1 cells rapamycin inhibited insulin-like growth factor-I (IGF-I)-stimulated phosphorylation of Thr(202) but not Tyr(204) and suppressed activation of p44/42 kinase activity. Down-regulation of raptor, which inhibits mTORC1 signaling, had a similar effect to rapamycin in blocking IGF-I-stimulated Tyr(204) phosphorylation. Rapamycin did not block maximal phosphorylation of Tyr(204) but retarded the rate of dephosphorylation of Tyr(204) following IGF-I stimulation. IGF-I stimulation of MEK1 phosphorylation (Ser(217/221)) was not inhibited by rapamycin. Higher concentrations of rapamycin (> or =100 ng/ml) were required to inhibit epidermal growth factor (EGF)-induced phosphorylation of p44/42 (Thr(202)). Rapamycin-induced inhibition of p44/42 (Thr(202)) phosphorylation by IGF-I was reversed by low concentrations of okadaic acid, suggesting involvement of protein phosphatase 2A (PP2A). Both IGF-I and EGF caused dissociation of PP2A catalytic subunit (PP2Ac) from p42. Whereas low concentrations of rapamycin (1 ng/ml) inhibited dissociation of PP2Ac after IGF-I stimulation, it required higher concentrations (> or =100 ng/ml) to block EGF-induced dissociation, consistent with the ability for rapamycin to attenuate growth factor-induced activation of p44/42. The effect of rapamycin on IGF-I or insulin activation of p44/42 was recapitulated by amino acid deprivation. Rapamycin effects altering the kinetics of p44/42 phosphorylation were completely abrogated in Rh1mTORrr cells that express a rapamycin-resistant mTOR, whereas the effects of amino acid deprivation were similar in Rh1 and Rh1mTORrr cells. These results indicate complex regulation of p44/42 by phosphatases downstream of mTORC1. This suggests a model in which mTORC1 modulates the phosphorylation of Thr(202) on p44/42 MAPKs through direct or indirect regulation of PP2Ac.
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PMID:mTORC1 signaling can regulate growth factor activation of p44/42 mitogen-activated protein kinases through protein phosphatase 2A. 1805 4

A growing body of evidence indicates that epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMC) may play an important role in the development and progression of peritoneal fibrosis during long-term peritoneal dialysis (PD) leading to failure of peritoneal membrane function. Here, we review our own observations and those of others on the mechanisms of EMT of HPMC and suggest potential therapeutic strategies to prevent EMT and peritoneal fibrosis during long-term PD. We found that high glucose and H2O2 as well as transforming growth factor-beta1 (TGF-beta1) induced EMT in HPMC and that high glucoseinduced EMT was blocked not only by inhibition of TGF-beta1 but also by antioxidants or inhibitors of mitogen-activated protein kinases (MAPK). Since MAPKs are downstream target molecules of reactive oxygen species (ROS), these data suggest that high glucose-induced generation of ROS and subsequent MAPK activation mediate high glucose-induced EMT in HPMC. We and others also observed that bone morphogenetic protein-7 (BMP-7) prevented EMT in HPMC. Glucose degradation products (GDP) were shown to play a role in inducing EMT. Involvement of a mammalian target of rapamycin (mTOR) in TGF-beta1-induced EMT has also been proposed in cultured HPMC. A better understanding of the precise mechanisms involved in EMT of HPMC may provide new therapeutic strategies for inhibiting peritoneal fibrosis in long-term PD patients.
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PMID:Mechanisms of epithelial-mesenchymal transition of peritoneal mesothelial cells during peritoneal dialysis. 1816 3

Inactivation of tumor suppressors is among the rate-limiting steps in carcinogenesis that occur during the tumor promotion stage. The translation inhibitor programmed cell death 4 (Pdcd4) suppresses tumorigenesis and invasion. Although Pdcd4 is not mutationally inactivated in human cancer, the mechanisms controlling Pdcd4 inactivation during tumorigenesis remain elusive. We report that tumor promoter 12-O-tetradecanoylphorbol-13-acetate exposure decreases protein levels of Pdcd4 in mouse skin papillomas and keratinocytes as well as in human HEK293 cells. This decrease is attributable to increased proteasomal degradation of Pdcd4 and is mediated by protein kinase C-dependent activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin-p70(S6K) and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling. Both Akt and p70(S6K) phosphorylate Pdcd4, allowing for binding of the E3-ubiquitin ligase beta-TrCP and consequently ubiquitylation. MEK-ERK signaling on the other hand facilitates the subsequent proteasomal degradation. We further show that Pdcd4 protein levels in vivo are limiting for tumor formation, establishing Pdcd4 as a haploinsufficient tumor suppressor in Pdcd4-deficient mice. Thus, because endogenous Pdcd4 levels are limiting for tumorigenesis, inhibiting signaling to Pdcd4 degradation may prove a valid strategy for cancer prevention and intervention.
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PMID:Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. 1829 47

Phosphatidylinositol-3-OH kinase (PI(3)K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3)K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta was mediated by mTOR through regulation of the transcription factor KLF2. PI(3)K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3)K and mTOR to match metabolism and trafficking.
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PMID:Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. 1842 96

This study examined the mechanisms by which transforming growth factor (TGF)-alpha regulates proliferation of mouse embryonic stem (ES) cells. TGF-alpha increased [3H] thymidine and BrdU incorporation in a time- (0-72 h) and dose-dependent (0-10 ng/ml) manner. TGF-alpha stimulated the phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70S6K1 and p44/42 mitogen-activated protein kinases (MAPKs). TGF-alpha also increased the protein levels of Notch, Notch intracellular domain, Hes-1 and Wnt1. However, TGF-alpha-induced DNA synthesis was blocked by inhibition of Akt, mTOR, p44/42 MAPKs and Notch. TGF-alpha increased the gene expression of c-jun, c-myc and c-fos. Moreover, TGF-alpha increased cyclin D/CDK 4 and cyclin E/CDK 2 levels, while decreasing p21cip1/waf1 and p27kip1, which were blocked by the inhibition of Akt, mTOR and Notch. In conclusion, TGF-alpha regulated DNA synthesis of mouse ES cells via PI3-K/Akt, p44/42 MAPKs and Notch/Wnt pathways.
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PMID:Regulation of DNA synthesis in mouse embryonic stem cells by transforming growth factor-alpha: involvement of the PI3-K/Akt and Notch/Wnt signaling pathways. 1842 29

Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Recent advances in the cellular and molecular biology of gliomas have enhanced our understanding of the role of receptor tyrosine kinases (RTK) and RTK-mediated signal transduction pathways in tumor initiation, maintenance, angiogenesis, and vascular proliferation. Special attention has been focused on targets such as epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and on pathways such as the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs known as small molecule inhibitors have been shown to modify the activity of these receptors and signaling pathways. Thus far, however, small molecule RTK inhibitor development has concentrated on a few RTK only, and drug activity has been comprehensively evaluated only in a limited number of different malignancies. One of the limiting factors for novel drug design and development is the incomplete knowledge of RTK functions in malignant glioma. This review summarizes current basic and clinical knowledge on the role of RTK in malignant glioma and on their importance as targets for new forms of therapy.
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PMID:Receptor tyrosine kinases as therapeutic targets in malignant glioma. 1847 93

We have previously reported the participation of mitogen-activated protein, Rho, and phosphoinositide-3 (PI3) kinases in separate pathways in serotonin (5-HT)-induced proliferation of pulmonary artery smooth muscle cells (SMCs). In this study, we investigated the possible participation of phospholipase D (PLD) and phosphatidic acid (PA) in this growth process. 5-HT stimulated a time-dependent increase in [(3)H]phosphatidylbutanol and PA generation. Exposure of SMCs to 1-butanol or overexpression of an inactive mutant of human PLD1R898R blocked 5-HT-induced proliferation. Furthermore, 1-butanol inhibited 5-HT activation of S6K1 and S6 protein, downstream effectors of mammalian target of rapamycin (mTOR), by 80 and 72%, respectively, and partially blocked activation of extracellular signal-regulated kinase (ERK) by 30% but had no effect on other associated signaling pathways. Exogenous PA caused cellular proliferation and revitalized cyclin D1 expression by 5-HT of the 1-butanol-treated cells. PA also reproduced activations by 5-HT of mTOR, S6K1, and ERK. Transfection with inactive human PLD1 reduced 5-HT-induced activation of S6K1 by approximately 50%. Inhibition of 5-HT receptor 2A (R 2A) with ketaserin blocked PLD activation by 5-HT. Inhibition with PI3-kinase inhibitor failed to block either activation of PLD by 5-HT or PA-dependent S6K1 phosphorylation. Taken together, these results indicate that ligation of the 5-HTR 2A by 5-HT initiates PLD activation in SMCs, and that its product, PA, is an early signaling molecule in 5-HT-induced pulmonary artery SMC proliferation. Signaling by PA produces its downstream effects primarily through the mTOR/S6K1 pathway and to a lesser extent through the ERK pathway. Hydrolysis of cell membrane lipid may be important in vascular effects of 5-HT.
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PMID:Phospholipase D signaling in serotonin-induced mitogenesis of pulmonary artery smooth muscle cells. 1862 11


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