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)

With age, skeletal muscle experiences substantial atrophy and weakness. Although resistance training can increase muscle size and strength, the myogenic response to exercise and the capacity for muscle hypertrophy in older humans and animals is limited. In the present study, we assessed the ability of muscle contractile activity to activate cellular pathways involved in muscle cell growth and myogenesis in adult (Y; 6 mo old) and aged (O; 30 mo old) Fischer 344 x Brown Norway rats. A single bout of rat hindlimb muscle contractile activity was elicited by high-frequency electrical stimulation (HFES) of the sciatic nerve. Plantaris (Pla) and tibialis anterior (TA) muscles were assayed for mammalian target of rapamycin (mTOR), 70-kDa ribosomal protein S6 kinase (p70(S6K)), and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and total protein either at baseline, immediately after, or 6 h after HFES. mTOR phosphorylation was elevated in Pla (1.3 +/- 0.3-fold, P < 0.05) immediately after HFES and to a lesser extent 6 h after HFES (0.6 +/- 0.1-fold, P < 0.05) in O rats. Post-HFES, p70(S6K) phosphorylation increased 1.2 +/- 0.3-fold in TA (P < 0.05) and remained elevated 6 h later (0.6 +/- 0.2-fold, P < 0.05) in O rats. ERK phosphorylation was lower in O rats immediately after exercise in both TA (11.1 +/- 2.9 vs. 2.1 +/- 0.5-fold, P < 0.05) and Pla (6.5 +/- 1.5 vs. 1.8 +/- 0.5-fold, P < 0.05) and returned to baseline by 6 h in both Y and O rats. Phosphorylation of mTOR, p70(S6K), and ERK1/2 are increased in skeletal muscle after a single bout of in situ muscle contractile activity in aged animals, and the response is less than that observed in adult animals. These observations suggest that the anabolic response to a single bout of contraction is attenuated with aging and may help explain the reduced capacity for hypertrophy in aged animals.
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PMID:Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle. 1503 70

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1alpha and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1alpha and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1alpha and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1alpha and VEGF-A expression. These results suggest that the PI3K/Akt/FRAP signaling pathway is required for HIF-1alpha and VEGF-A expression induced by 4-OHE2, whereas the MAPK pathway is not required. The finding that induction of HIF-1alpha and VEGF-A expression occurs via the activation of the PI3K/Akt/FRAP signaling pathway could be an important mechanism of 4-OHE2-induced carcinogenesis.
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PMID:4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells. 1505 Apr 14

Activation of 40S ribosomal protein S6 kinases (S6Ks) is mediated by anabolic signals triggered by hormones, growth factors, and nutrients. Stimulation by any of these agents is inhibited by the bacterial macrolide rapamycin, which binds to and inactivates the mammalian target of rapamycin, an S6K kinase. In mammals, two genes encoding homologous S6Ks, S6K1 and S6K2, have been identified. Here we show that mice deficient for S6K1 or S6K2 are born at the expected Mendelian ratio. Compared to wild-type mice, S6K1(-/-) mice are significantly smaller, whereas S6K2(-/-) mice tend to be slightly larger. However, mice lacking both genes showed a sharp reduction in viability due to perinatal lethality. Analysis of S6 phosphorylation in the cytoplasm and nucleoli of cells derived from the distinct S6K genotypes suggests that both kinases are required for full S6 phosphorylation but that S6K2 may be more prevalent in contributing to this response. Despite the impairment of S6 phosphorylation in cells from S6K1(-/-)/S6K2(-/-) mice, cell cycle progression and the translation of 5'-terminal oligopyrimidine mRNAs were still modulated by mitogens in a rapamycin-dependent manner. Thus, the absence of S6K1 and S6K2 profoundly impairs animal viability but does not seem to affect the proliferative responses of these cell types. Unexpectedly, in S6K1(-/-)/S6K2(-/-) cells, S6 phosphorylation persisted at serines 235 and 236, the first two sites phosphorylated in response to mitogens. In these cells, as well as in rapamycin-treated wild-type, S6K1(-/-), and S6K2(-/-) cells, this step was catalyzed by a mitogen-activated protein kinase (MAPK)-dependent kinase, most likely p90rsk. These data reveal a redundancy between the S6K and the MAPK pathways in mediating early S6 phosphorylation in response to mitogens.
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PMID:S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. 1506 Jan 35

With tendency to invade rapidly in the brain, malignant gliomas are very resistant to conventional therapies including radiation and chemotherapy. Recent advances in genetic and molecular techniques have made it possible to define characteristic molecular profiles of malignant gliomas. Based on the list of the molecules closely related to glioblastoma tissues, we reviewed strategies targeting them. Target molecules extensively studied include EGFR, PTEN, telomerase and signal pathway modulators for Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Therapies targeting specific molecules may result in killing tumor cells effectively while keeping normal cells intact.
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PMID:Molecular targeting for malignant gliomas (Review). 1506 31

Previous studies have shown that the synthesis and stability of milk protein mRNAs are regulated by lactogenic hormones. We demonstrate here in cultured mouse mammary epithelial cells (CID 9) that insulin plus prolactin also synergistically increases the rate of milk protein mRNA translation. Insulin alone stimulates synthesis of both milk and nonmilk proteins, whereas prolactin alone has no effect, but insulin plus prolactin selectively stimulate synthesis of milk proteins more than insulin alone. The increase in beta-casein mRNA translation is also reflected in a shift to larger polysomes, indicating an effect on translational initiation. Inhibitors of the phosphatidylinositol 3-kinase, mammalian target of rapamycin, and MAPK pathways block insulin-stimulated total protein and beta-casein synthesis but not the synergistic stimulation. Conversely, cordycepin abolishes synergistic stimulation of protein synthesis without affecting insulin-stimulated translation. The poly(A) tract of beta-casein mRNA progressively increases from approximately 20 to about 200 A residues over 30 min of treatment with insulin plus prolactin. The 3'-untranslated region of beta-casein mRNA containing an unaltered cytoplasmic polyadenylation element is sufficient for the translational enhancement and mRNA-specific polyadenylation, based on transient transfection of cells with a reporter construct. Insulin and prolactin stimulate cytoplasmic polyadenylation element binding protein phosphorylation with no increase of cytoplasmic poly(A) polymerase activity.
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PMID:Insulin and prolactin synergistically stimulate beta-casein messenger ribonucleic acid translation by cytoplasmic polyadenylation. 1507 Oct 91

Increased cell proliferation, which is a hallmark of aggressive malignant neoplasms, requires a general increase in protein synthesis and a specific increase in the synthesis of replication-promoting proteins. Transient increase in the general protein synthesis rate, as well as preferential translation of specific mRNAs coding for growth promoting proteins (e.g. cyclin D1), takes place during normal mitogenic response. A number of extensively studied growth signal transduction pathways (Ras, PI3K, MAPK, mTOR-dependent pathways) activate the function and expression of various components of the translational machinery. In abnormal situations, constitutive activation of signal transduction pathways (e.g. oncogenic activation of Ras or Myc) leads to continuous upregulation of key elements of translational machinery. On the other hand, tumor suppressor genes (p53, pRb) downregulate ribosomal and tRNA synthesis, and their inactivation results in uncontrolled production of these translational components. During recent years, a significant effort has been dedicated to determining whether expression of translation factors is increased in human tumors using clinical biopsy specimens. The results of these studies indicate that expression of particular translation initiation factors is not always increased in human neoplasms. The pattern of expression is characteristic for a particular tumor type. For example, eIF-4E is usually increased in bronchioloalveolar carcinomas but not in squamous cell carcinomas of the lung. Interestingly, in certain highly proliferative and aggressive neoplasms (e.g. squamous cell carcinoma of the lung, melanoma), the expression of eIF-4E is barely detectable. These findings suggest that mechanisms for increasing general protein synthesis in various neoplasms differ significantly. Finally, the possibility of qualitative alterations in the translational machinery, rather than a simple increase in the activity of its components, is discussed along with the possibility of targeting those qualitative differences for tumor therapy.
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PMID:The role of translation in neoplastic transformation from a pathologist's point of view. 1509 73

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome with manifestations that can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). We found that tuberin expression increases p42/44 MAPK phosphorylation and B-Raf kinase activity. Short interfering RNA down-regulation of tuberin decreased the p42/44 MAPK phosphorylation and B-Raf activity. Expression of Rheb, the target of the GTPase-activating domain of tuberin, inhibited wild-type B-Raf kinase but not activated forms of B-Raf. The interaction of endogenous Rheb with B-Raf was enhanced by serum and by Ras overexpression. A farnesylation-defective mutant of Rheb co-immunoprecipitated with and inhibited B-Raf but did not activate ribosomal protein S6 kinase, indicating that farnesylation is not required for B-Raf inhibition by Rheb and that B-Raf inhibition and S6 kinase activation are separable activities of Rheb. Consistent with this, inhibition of B-Raf and p42/44 MAPK by Rheb was resistant to rapamycin in contrast to Rheb activation of S6 kinase, which is rapamycin-sensitive. Taken together these data demonstrate that inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin.
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PMID:Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. 1515 Feb 71

While pancreatic protein synthesis and the initiation of translation are regulated by hormones and neurotransmiters, whether the elongation process is also regulated is unknown. Stimulatory doses of cholecystokinin (CCK) (100 pM), bombesin (10 nM), and carbachol (10 microM) increased elongation rates (measured as ribosomal half-transit time) in pancreatic acini in vitro. At the same time these secretagogues reduced elongation factor 2 (eEF2) phosphorylation, the main factor known to regulate elongation, and increased the phosphorylation of the eEF2 kinase. The mTOR inhibitor rapamycin reversed the dephosphorylation of eEF2 induced by CCK, as did treatment with the p38 MAPK inhibitor SB202190, the MEK inhibitor PD98059, and the phosphatase inhibitor calyculin A. Neither rapamycin, SB202190, PD98059 nor calyculin A had an effect on CCK mediated eEF2 kinase phosphorylation. Translation elongation in pancreatic acinar cells is likely regulated by eEF2 through the mTOR, p38, and MEK pathways, and modulated through PP2A.
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PMID:Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini. 1515 53

Decreased glutathione (GSH) levels and gamma-glutamylcysteine ligase (GCL) activity have been observed in diabetic patients, and insulin reportedly increases GSH synthesis via increased GCL catalytic subunit (GCLC) gene expression. The signaling pathways responsible for mediating insulin effects on GCLC expression and GSH levels, however, are unknown. The signaling pathways involved in the regulation of GSH synthesis in response to insulin were examined in primary cultured rat hepatocytes. GSH levels, GCL activity, GCLC protein, and mRNA levels were increased to 140, 160, 600, and 340% of that monitored in untreated cells, respectively, in hepatocytes cultured with 100 nM insulin. The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [2-(4-morpholinyl)-9-phenyl-4H-1-benzopyran-4-one], dominant-negative Akt, or rapamycin, an inhibitor of mTOR (mammalian target of rapamycin) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin-mediated increase in GCLC protein and GSH levels. Although the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase, p38 MAPK, and JNK (c-Jun N-terminal kinase) were activated in response to insulin, PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of JNK, and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK, failed to inhibit the insulin-mediated increase in GCLC protein levels. In conclusion, these data show that insulin signaling pathways involving PI3K/Akt/p70S6K, but not MAPKs, are active in the insulin-mediated regulation of GSH synthesis via increased GCLC expression.
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PMID:Insulin signaling regulates gamma-glutamylcysteine ligase catalytic subunit expression in primary cultured rat hepatocytes. 1516 30

Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.
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PMID:IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells. 1518 2


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