Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.
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PMID:Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. 1676 20

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPARgamma activation state has recently been shown to modulate beta-amyloid peptide (Abeta) production in cellular models relevant to Alzheimer's disease. Here, we report the effect of troglitazone, a thiazolidinedione, in cells expressing 4-repeat tau. A 24 h treatment with troglitazone significantly reduced phosphorylation of tau at Ser202 and Ser396/404, residues of early and later stages of neurofibrillary tangle accumulation in Alzheimer's disease and other neurodegenerative disorders. Under the same experimental conditions the level of tau did not change. In our cellular model, troglitazone appeared to enhance 3'-phosphoinositide-dependent protein kinase 1 (PDK1) nuclear translocation, resulting in a decrease in cytosolic phosphorylated 70 kDa ribosomal protein kinase (p70S6) and phosphorylated mammalian target of rapamycin (mTor). Furthermore, PPARgamma transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPARgamma-dependent/independent mechanism involving an Akt/glycogen synthase kinase-3(GSK-3beta)-independent signalling cascade: PDK1/p70S6K/mTor.
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PMID:Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells. 1678 14

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes.
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PMID:Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. 1691 7

Microglia of the central nervous system serve a variety of functions that may ultimately lead to the development or detriment of neighboring neuronal and vascular cells. These scavengers of the nervous system have been associated with a variety of neurodegenerative disorders, but the toxic potential of microglia is equally balanced by the protective nature of these cells to exclude foreign microorganisms and promote new tissue proliferation and reorganization. To this extent, our work outlines a series of endogenous microglial cellular pathways that can constitute protection for microglia against during oxygen-glucose deprivation (OGD). We demonstrate in both primary microglia and the microglial cell line EOC 2 that endogenous microglial protection against OGD relies upon the activation and expression of the phosphatidylinositol 3-kinase pathways of mammalian target of rapamycin (mTOR) and protein kinase B (Akt1), since pharmacological inhibition of mTOR or Akt1 as well as the gene silencing of Akt1 protein expression leads to significantly increased microglial apoptotic cell injury, DNA fragmentation, and membrane phosphatidylserine exposure. The mTOR pathway may offer endogenous protection through mechanisms that do not entirely rely upon inhibition of glycogen synthase kinase-3beta (GSK-3beta) activity while Akt1 appears to converge upon the necessary blockade of GSK-3beta. Closely aligned to these endogenous protective mechanisms is the subcellular presence and nuclear translocation of nuclear factor-kappaB p65 (NF-kappaB p65), since microglial cell injury is significantly increased during the gene silencing of NF-kappaB p65. Elucidating the underlying pathways that can afford endogenous protection and maintain functional integrity of microglia should offer new prospects for the treatment of a broad range of nervous system disorders.
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PMID:The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. 1720

Insulin-like growth factor-1 (IGF-1) has been shown to induce skeletal muscle hypertrophy, to prevent the loss of muscle mass with ageing and to improve the muscle phenotype of dystrophic mice. We previously developed a model of IGF-1-induced hypertrophy of human myotubes, in which hypertrophy was not only characterized by an increase in myotube size and myosin content but also by an increased recruitment of reserve cells for fusion. Here, we describe a new mechanism of IGF-1-induced hypertrophy by demonstrating that IGF-1 signals exclusively to myotubes but not to reserve cells, leading, under the control of the transcription factor NFATc2, to the secretion of IL-13 that will secondly recruit reserve cells for differentiation and fusion. In addition, we show that IGF-1 also signals to myotubes to stimulate protein metabolism via Akt by (1) activating the mTOR-p70S6K-S6 pathway and inhibiting GSK-3beta, both involved in the control of protein translation, and (2) inhibiting the Foxo1-atrogin-1 protein degradation pathway.
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PMID:IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes. 1726 50

Cathepsin D (CD) is an essential lysosomal protease and mice lacking this enzyme exhibit neuropathology similar to that observed in brains of patients with neuronal ceroid lipofuscinosces (NCL/Batten disease), a group of autosomal recessive pediatric neurodegenerative diseases. CD-deficient (CD-/-) brains exhibit a dramatic induction of autophagic stress as defined by the aberrant accumulation of autophagosomes, which is concomitant with markers of apoptosis. However, the signaling abnormalities which lead to CD deficiency-induced neurodegeneration are poorly defined. Since phosphatidylinositol-3 kinase (PI3-K) is known to regulate both apoptosis and autophagy, PI3-K-mediated signaling events were assessed in CD-/- brain at P14 and P25-26. Compared to WT littermate controls, CD-/- cortical neurons exhibited a widespread decrease in phosphorylation of Akt (inactivation) and GSK3beta (disinhibition) at P25-26, while levels of total Akt and GSK3beta remained unchanged. This P25-26-specific decrease in phosphorylation of Akt and GSK-3beta in CD-/- brain coincided temporally with markers of apoptosis but followed the induction of autophagic stress observed at both P14 and P25-26. In addition, levels and/or activation of mTOR and Beclin were not affected by CD deficiency, suggesting that the accumulation of autophagosomes is not due to an increased synthesis of autophagosomes but rather from an inhibition of autophagosome recycling, due most likely to a compromise in lysosome function. Together these observations indicate a pronounced decrease in pro-survival PI3-K signaling in CD-/- brain that may contribute to autophagic stress-induced and apoptotic neuropathology.
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PMID:Altered regulation of phosphatidylinositol 3-kinase signaling in cathepsin D-deficient brain. 1729 99

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.
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PMID:TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. 1731 37

Estivation, a state of aerobic dormancy, facilitates survival during adverse environmental conditions and is characterized at the molecular level by regulatory protein phosphorylation. The Akt (protein kinase B) signaling pathway regulates diverse responses in cells and the present study analyzes its role in the estivating desert snail Otala lactea. Kinetic analysis (maximal velocity, substrate affinities) determined that Akt was activated in tissues of estivating snails and Western blotting and in vitro incubations promoting changes to Akt phosphorylation state both confirmed that higher amounts of active (phosphorylated Ser473) Akt were present during estivation. Akt protein stability was also enhanced during estivation as assessed from urea denaturation studies. Multiple downstream targets of Akt were differentially regulated during estivation. Estivating animals showed elevated levels of phosphorylated FOXO3a (Ser253) and BAD (Ser136), no change in mTOR (Ser2481 and Ser2448), and reduced amounts of phosphorylated glycogen synthase kinase-3 (GSK-3) beta subunit (Ser9). Kinetic analysis of GSK-3 showed 1.5-1.7 fold higher activities in estivating snails coupled with increased GSK-3 substrate affinities in hepatopancreas. The data suggest an active role for Akt signaling during estivation emphasizing anti-apoptotic actions but uncoupling growth/proliferation actions to help achieve life extension on a limited energy budget.
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PMID:Akt and its downstream targets play key roles in mediating dormancy in land snails. 1761 Nov 33

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

Zinc (Zn) is an essential trace element that functions in cellular signaling. The mammalian target of rapamycin (mTOR) regulates the initiation of protein synthesis. The objective of this study was to determine whether Zn could stimulate protein phosphorylation in the mTOR pathway in vivo. Mice (C57BL/6J, n = 30) were fed Zn marginal diets (ZM, 5 mg/kg) for 4 weeks, followed by fasting (F) and/or refeeding with ZM or Zn supplemental (300 mg/kg, ZS) diets for 3 or 6 h. Plasma insulin was greater (P < 0.05) in refed animals as compared to F animals. Protein phosphorylation was detected using multiplex analysis and Western blotting. Multiplex analysis indicated greater (P < 0.05) p70 S6 kinase (p70S6K) and glycogen synthase kinase 3 (GSK-3 alpha/beta) phosphorylation in livers from 6-h refed ZS animals as compared to F animals. Western blots indicated increased (P < 0.05) Akt (Ser 473) phosphorylation in skeletal muscle from animals refed ZS diets for 3 and 6 h as compared to F animals. The ZS diet affected phosphorylation of GSK-3 (alpha/beta) in liver, as 3-h ZS refed animals had greater (P < 0.01) phosphorylation than F animals. These findings indicate that Zn may contribute to the initiation of protein synthesis as a signaling molecule in vivo.
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PMID:Effect of supplemental dietary zinc on the mammalian target of rapamycin (mTOR) signaling pathway in skeletal muscle and liver from post-absorptive mice. 1784 32


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