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)

Adipose tissue is a major site for whole-body glutamine synthesis and we are investigating mechanisms and regulation of glutamine transport across the adipocyte membrane. Glutamine transport in adipocytes includes both high- and low-affinity Na+-dependent components (consistent with observed expression of ASCT2 and ATA2/SAT2 transporter mRNAs respectively) and a Na+-independent transport component (consistent with observed expression of LAT1/2 transporter mRNAs). Hypo-osmotic (235 mosmol/kg) swelling of adipocytes transiently stimulated glutamine uptake (180% increase at 0.05 mM glutamine) within 5 mins. Stimulation was blocked by the tyrosine kinase inhibitor genistein and the MAP kinase pathway inhibitors PD98059 and SB203580, but not by wortmannin (PI 3-kinase inhibitor) or rapamycin (mTOR pathway inhibitor). Cell-swelling also stimulated uptake of glucose but not MeAIB (indicating that ASCT2 rather than ATA2 was stimulated by swelling). Insulin (66 nM) treatment for up to 1 h stimulated Na+-dependent glutamine transport and increased adipocyte water space. Activation of the ERK1-2 MAP kinase pathway by cell swelling or insulin may be important for rapid activation of the ASCT2 glutamine transporter in adipocytes. Insulin may also exert a minor additional stimulatory effect on adipocyte glutamine transport indirectly via cell swelling. The mechanisms regulating glutamine transport in adipose tissue are distinct from those in other major sites of glutamine turnover in the body (notably liver and skeletal muscle).
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PMID:Mechanisms of glutamine transport in rat adipocytes and acute regulation by cell swelling. 1168 15

Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes.
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PMID:Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. 1221 1

Arsenite is ubiquitous in the environment, particularly in the form of contaminated water. Although this metal is a known human carcinogen, its exact mechanism of action remains unclear. P70S6K1 phosphorylates the ribosomal 40S protein leading to increased protein translation, and is an important regulator of cell growth and proliferation. Hypoxia inducible factor-1 (HIF-1) is a basic helix-loop-helix transcription factor composed of two subunits, HIF-1alpha and HIF-1beta. HIF-1 activates the transcription of a number of genes that mediate angiogenesis and tumor formation. In this study we demonstrated that arsenite treatment increased levels of p70S6K1 phosphorylation and p70S6K1 activity in a PI3K and mTOR sensitive manner. We have also shown that arsenite specifically induces HIF-1alpha, but not HIF-1beta, protein levels in prostate cancer cells in a mTOR-dependent manner.
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PMID:Arsenite induces p70S6K1 activation and HIF-1alpha expression in prostate cancer cells. 1497 42

Mammalian target of rapamycin (mTOR) mediates a signaling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth rate, participating to a versatile checkpoint that inspects the energy status of the cell. The pathway is activated by branched-chain amino acids (BCAA), leucine being the most effective, whereas amino acid dearth and ATP shortage lead to its deactivation. Glutamine- or amino acid-deprivation and hyperosmotic stress induce a fast cell shrinkage (with marked decrease of the intracellular water volume) associated to mTOR-dependent S6K1 dephosphorylation. Using cultured Jurkat cells, we have measured the changes of cell content and intracellular concentration of ATP, of relevant amino acids (BCAA) and of ninhydrin-positive substances (NPS, as measure of NH(2)-bearing organic osmolytes) under conditions that deactivate (leucine-deprivation, glutamine-deprivation, amino acid withdrawal, sorbitol-induced hyperosmotic stress) or reactivate a previously deactivated, mTOR-S6K1 pathway. We have also assessed the mitochondrial function by measurements of mitochondrial transmembrane potential in cells subjected to hypertonic stress. Our results indicate that diverse control signals converge on the mTOR-S6K1 signaling pathway. In the presence of adequate energy resources, the pathway senses the amino acid availability as inward transport of effective amino acids (as BCAA and especially leucine), but its activation occurs only in the presence of an extracellular amino acid complement, with glutamine as obligatory component, and does not tolerate decrements of cell water volume incapable of maintaining adequate intracellular physicochemical conditions.
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PMID:Amino acid signaling through the mammalian target of rapamycin (mTOR) pathway: Role of glutamine and of cell shrinkage. 1560 14

Eccentric contractions (EC) are known to result in muscle hypertrophy, potentially through activation of the Akt-mammalian target of rapamycin-p70 S6 kinase (p70S6K) signaling pathway. Previous work has also demonstrated that EC result in the opening of stretch-activated channels (SAC), and inhibition of these channels resulted in an attenuation of EC-induced muscle hypertrophy. The purpose of this study was to test the hypothesis that a known intracellular pathway directly associated with muscle hypertrophy is coupled to the opening of SAC. Specifically, we measured the activation of the Akt, GSK-3beta, p70S6K, and ribosomal protein S6 following a single bout of EC in the rat tibialis anterior (TA) muscle. The TA muscles performed four sets of six repetitions of EC. In vivo blockade of SAC was performed by a continuous oral treatment with streptomycin in the drinking water (4 g/l) or by intravenous infusion of 80 micromol/kg gadolinium (Gd3+). EC increased the degree of Akt and p70S6K phosphorylation in the TA muscle, whereas in animals in which SAC had been inhibited, there was a reduced capacity for EC to induce Akt or p70S6K phosphorylation. Accompanying this reduced activation of Akt and p70S6K was a failure to phosphorylate GSK-3beta or S6 when SAC were inhibited. The results from these data indicate the necessity of functional SAC for the complete activation of Akt and p70S6K pathway in response to EC.
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PMID:Inhibition of stretch-activated channels during eccentric muscle contraction attenuates p70S6K activation. 1617 99

Cellular accumulation of creatine is accomplished by the Na(+), Cl(-), and creatine transporter CreaT (SLC6A8). The mammalian target of rapamycin (mTOR) is a kinase stimulating cellular nutrient uptake. The present experiments explored whether SLC6A8 is regulated by mTOR. In Xenopus oocytes expressing SLC6A8 but not in water injected oocytes, creatine-induced a current which was significantly enhanced by coexpression of mTOR. Kinetic analysis revealed that mTOR enhanced maximal current without significantly altering affinity. Preincubation of the oocytes for 32 h with rapamycin (50 nM) decreased the creatine-induced current and abrogated its stimulation by mTOR. The effect of mTOR on CreaT was blunted by additional coexpression of the inactive mutant of the serum and glucocorticoid-inducible kinase (K119N)SGK1 and mimicked by coexpression of wild type SGK1. In conclusion, mTOR stimulates the creatine transporter SLC6A8 through mechanisms at least partially shared by the serum and glucocorticoid-inducible kinase SGK1.
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PMID:Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR. 1646 92

The aim of this study was to evaluate the effect of nutritional deprivation (ND) on signal transduction pathways influencing the translational apparatus in the diaphragm muscle. Male rats were divided into two groups: 1) 20% of usual food intake for 4 days (ND) with water provided at libitum and 2) free-eating control (Ctl). Total protein and RNA were extracted from the diaphragm. Insulin-like growth factor I mRNA was analyzed by RT-PCR. Protein analyses of key cytoplasmic proteins for three signaling pathways deemed important in influencing protein turnover [phosphatidylinositol 3-kinase- Akt-mammalian target of rapamycin, P13K/Akt/glycogen synthase kinase (GSK)-3, and MAPK-ERK] were performed by Western blot. Body weight decreased 30% in ND and increased 17% in Ctl animals. Diaphragm mass decreased 29% in ND animals. Muscle insulin-like growth factor I mRNA abundance was reduced 63% in ND animals. ND resulted in a 55% reduction in phosphorylated (Ser473) Akt. Phosphorylation of mammalian target of rapamycin at Ser2448 was reduced by 85% in ND animals. Downstream effectors important in translation initiation were also affected by ND. Phosphorylated (Thr389) 70-kDa ribosomal protein S6 kinase was significantly reduced (35%) by ND. ND also resulted in significant dephosphorylation of the translational repressor initiation factor 4E-binding protein 1. Phosphorylation of GSK-3alpha (Ser21) and GSK-3beta (Ser9) was increased 55 and 45%, respectively, with ND. Phosphorylation of ERK1 (Thr202) and ERK2 (Tyr204), p44 and p42, respectively, was reduced 64 and 55%, respectively, with ND. Total protein concentration for all signaling intermediates of the three pathways was preserved. We conclude that short-term ND altered the phosphorylation states of key proteins of several pathways involved in protein turnover. This forms the framework for future studies aimed at identifying therapeutic targets in the management of short-term nutritionally induced cachectic states.
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PMID:Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover. 1648 60

The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity x tumor volume) in a dose-dependent fashion. Polyphenon E (2% wt/wt) in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.
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PMID:Efficacy of polyphenon E, red ginseng, and rapamycin on benzo(a)pyrene-induced lung tumorigenesis in A/J mice. 1653 26

Aquaporin 3 (AQP3), a membrane protein, is known to permeabilize water and other small molecules such as glycerol and urea and is localized in the bowel, skin, kidney, and erythrocytes. Since glycerol is a nutrient and serves as a source material in glycolytic metabolism, absorption of glycerol in the gastrointestinal tract may be under some control. Therefore we first investigated whether insulin regulating the glycolytic pathway took part in glycerol transport through AQP3 in the gastrointestinal tract and found that insulin significantly suppressed mRNA and protein expressions of AQP3 in Caco-2 cells. The antidiabetic drugs troglitazone and tolbutamide were also observed to suppress significantly AQP3 expression, but the biguanides metformin and buformin did not induce such suppression. Epinephrine was found to increase expression of AQP3, although glucagon showed no change of expression. Wortmannin and rapamycin were demonstrated to deactivate suppression of AQP3 expression by insulin and troglitazone, suggesting that the signal transducers, phosphoinositide 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), are involved in the signal pathway for regulating transcription of AQP3.
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PMID:Regulators for blood glucose level affect gene expression of aquaporin 3. 1665 33

Adequate phosphate homeostasis is of critical importance for a wide variety of functions including bone mineralization and energy metabolism. Phosphate balance is a function of intestinal absorption and renal elimination, which are both under tight hormonal control. Intestinal phosphate absorption is accomplished by the Na(+), phosphate cotransporter NaPi IIb (SLC34A2). Signaling mechanisms mediating hormonal regulation of SLC34A2 are incompletely understood. The mammalian target of rapamycin (mTOR) is a kinase regulating a variety of nutrient transporters. The present experiments explored whether mTOR regulates the activity of SLC34A2. In Xenopus oocytes expressing SLC34A2 but not in water injected oocytes phosphate (1 mM) induced a current (Ip) which was significantly enhanced by coexpression of mTOR. Preincubation of the oocytes for 24 h with rapamycin (50 nM) did not significantly affect Ip in the absence of mTOR but virtually abolished the increase of Ip following coexpression of mTOR. The wild type serum and glucocorticoid inducible kinase SGK1 and the constitutively active (S422D)SGK1 similarly stimulated Ip, an effect again reversed by rapamycin. Coexpression of the inactive mutant of the serum and glucocorticoid inducible kinase (K119N)SGK1 significantly decreased Ip and abrogated the stimulating effect of mTOR on Ip. In conclusion, mTOR and SGK1 cooperate in the stimulation of the intestinal phosphate transporter SLC34A2.
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PMID:Stimulation of the intestinal phosphate transporter SLC34A2 by the protein kinase mTOR. 1673 Jun 58


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