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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.
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PMID:The role of CNS fuel sensing in energy and glucose regulation. 1749 9

Excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance associated with obesity and type 2 diabetes mellitus. The aim of this study was to investigate direct effects of palmitate on insulin signaling in hepatocytes. The ability of metformin to reverse changes induced by palmitate was also studied. Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. By contrast, the mTOR protein kinase was overstimulated in cells incubated with palmitate. Hepatocytes cultured with palmitate displayed hyperphosphorylation of IRS-1 at Ser residues 632/635, known to be phosphorylated by mTOR. Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. These data suggest a link between an oversupply of fatty acid to hepatocytes, a disproportionate stimulation of mTOR/S6K1, and resistance to insulin.
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PMID:Activation of mammalian target of rapamycin complex 1 and insulin resistance induced by palmitate in hepatocytes. 1769 34

High glucose and high insulin, pathogenic factors in type 2 diabetes, induce rapid synthesis of the matrix protein laminin-beta1 in renal proximal tubular epithelial cells by stimulation of initiation phase of mRNA translation. We investigated if elongation phase of translation also contributes to high glucose and high insulin induction of laminin-beta1 synthesis in proximal tubular epithelial cells. High glucose or high insulin rapidly increased activating Thr56 dephosphorylation of eEF2 and inactivating Ser366 phosphorylation of eEF2 kinase, events that facilitate elongation. Studies with inhibitors showed that PI3 kinase-Akt-mTOR-p70S6 kinase pathway controlled changes in phosphorylation of eEF2 and eEF2 kinase induced by high glucose or high insulin. Renal cortical homogenates from db/db mice in early stage of type 2 diabetes showed decrease in eEF2 phosphorylation and increment in eEF2 kinase phosphorylation in association with renal hypertrophy and glomerular and tubular increase in laminin-beta1 content. Rapamycin, an inhibitor of mTOR, abolished diabetes-induced changes in phosphorylation of eEF2, eEF2 kinase, and p70S6 kinase and ameliorated renal hypertrophy and laminin-beta1 protein content, without affecting hyperglycemia. These data show that mTOR is an attractive target for amelioration of diabetes-induced renal injury.
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PMID:Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. 1799 18

Subjects with Type II diabetes mellitus are more vulnerable in developing colorectal tumors, suggesting that hyperinsulinemia may stimulate proto-oncogene expression, and the existence of crosstalk between insulin signaling and pathways that are involved in colorectal tumor formation. We show here that insulin stimulates cell proliferation and c-Myc expression in colon cancer cell lines HT29 and Caco-2, intestinal non-cancer cell line IEC-6, and primary fetal rat intestinal cell (FRIC) cultures. The effect of insulin was blocked by phosphoinositide-3 Kinase (PI3K) inhibition, but only partially attenuated by inhibition of Protein kinase B (PKB), indicating the existence of both PKB-dependent and -independent mechanisms. The PKB-dependent mechanism of insulin-stimulated c-Myc expression in HT29 cells was shown to involve the activation of mTOR in c-Myc translation. In the investigation of the PKB-independent mechanism, we found that insulin-induced nuclear translocation of beta-catenin (beta-cat), an effector of Wnt signaling. Furthermore, insulin stimulated the expression of TopFlash, a Wnt-responsive reporter gene. Finally, chromatin immunoprecipitation (ChIP) detected significant increases in the binding of beta-cat to two TCF binding sites of the human c-Myc promoter following insulin treatment. Our observations support the existence of crosstalk between insulin and Wnt signaling pathways, and suggest that the crosstalk involves a PKB-independent mechanism.
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PMID:Both Wnt and mTOR signaling pathways are involved in insulin-stimulated proto-oncogene expression in intestinal cells. 1799 59

Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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PMID:Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. 1800 25

Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca(2+) ([Ca(2+)](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca(2+)](i) increases the direct binding of Ca(2+)/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.
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PMID:Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. 1846 Mar 36

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.
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PMID:The mTOR pathway and its role in human genetic diseases. 1859 80

High glucose (30 mM) and high insulin (1 nM), pathogenic factors of type 2 diabetes, increased mRNA expression and synthesis of lamininbeta1 and fibronectin after 24 h of incubation in kidney proximal tubular epithelial (MCT) cells. We tested the hypothesis that inactivation of glycogen synthase kinase 3beta (GSK3beta) by high glucose and high insulin induces increase in synthesis of laminin beta1 via activation of eIF2Bepsilon. Both high glucose and high insulin induced Ser-9 phosphorylation and inactivation of GSK3beta at 2 h that lasted for up to 48 h. This was associated with dephosphorylation of eIF2Bepsilon and eEF2, and increase in phosphorylation of 4E-BP1 and eIF4E. Expression of the kinase-dead mutant of GSK3beta or constitutively active kinase led to increased and diminished laminin beta1 synthesis, respectively. Incubation with selective kinase inhibitors showed that high glucose- and high insulin-induced laminin beta1 synthesis and phosphorylation of GSK3beta were dependent on PI 3-kinase, Erk, and mTOR. High glucose and high insulin augmented activation of Akt, Erk, and p70S6 kinase. Dominant negative Akt, but not dominant negative p70S6 kinase, inhibited GSK3beta phosphorylation induced by high glucose and high insulin, suggesting Akt but not p70S6 kinase was upstream of GSK3beta. Status of GSK3beta was examined in vivo in renal cortex of db/db mice with type 2 diabetes at 2 weeks and 2 months of diabetes. Diabetic mice showed increased phosphorylation of renal cortical GSK3beta and decreased phosphorylation of eIF2Bepsilon, which correlated with renal hypertrophy at 2 weeks, and increased laminin beta1 and fibronectin protein content at 2 months. GSK3beta and eIF2Bepsilon play a role in augmented protein synthesis associated with high glucose- and high insulin-stimulated hypertrophy and matrix accumulation in renal disease in type 2 diabetes.
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PMID:Glycogen synthase kinase 3beta is a novel regulator of high glucose- and high insulin-induced extracellular matrix protein synthesis in renal proximal tubular epithelial cells. 1870 53

Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.
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PMID:The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. 1883 43

The genes TSC1 and TSC2, encoding hamartin and tuberin, respectively, have been shown to be involved in the development of the autosomal dominantly inherited tumor syndrome tuberous sclerosis (TSC). However, inactivation of these genes has also been demonstrated to be associated with sporadic bladder cancer, ovarian and gall bladder carcinoma, non-small-cell carcinoma of the lung, breast cancer, pancreatic cancer, astrocytoma, xanthoastrocytoma, ependymomas, oral squamous cell carcinoma and endometrial cancer. The hamartin/tuberin protein complex plays a central role in the regulation of the mammalian target of rapamycin (mTOR) signalling network. A wide variety of components of the mTOR cascade have been demonstrated to be involved in many different human cancers. Mutations in several mTOR pathway component genes are known to cause specific monogenic human genetic diseases and this signalling cascade has been shown to be of relevance for Alzheimer's disease, type 2 diabetes, obesity and hypertrophy. Consequently, e.g. clinical trials for the treatment with rapamycin, a negative regulator of mTOR, of hamartomas in TSC have already been initiated. Now the first evidence is provided for an involvement of the TSC genes in acute leukemia.
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PMID:New insights into the role of the tuberous sclerosis genes in leukemia. 1925 Jun 71


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