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)

Feeding promotes protein accretion in skeletal muscle through a stimulation of the mRNA translation initiation phase of protein synthesis either secondarily to nutrient-induced rises in insulin or owing to direct effects of nutrients themselves. The present set of experiments establishes the effects of meal feeding on potential signal transduction pathways that may be important in accelerating mRNA translation initiation. Gastrocnemius muscle from male Sprague-Dawley rats trained to consume a meal consisting of rat chow was sampled before, during, and after the meal. Meal feeding enhanced the assembly of the active eIF4G.eIF4E complex, which returned to basal levels within 3 h of removal of food. The increased assembly of the active eIF4G.eIF4E complex was associated with a marked 10-fold rise in phosphorylation of eIF4G(Ser(1108)) and a decreased assembly of inactive 4E-BP1.eIF4E complex. The reduced assembly of 4E-BP1.eIF4E complex was associated with a 75-fold increase in phosphorylation of 4E-BP1 in the gamma-form during feeding. Phosphorylation of S6K1 on Ser(789) was increased by meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of mammalian target of rapamycin (mTOR) on Ser(2448) or Ser(2481), an upstream kinase responsible for phosphorylating both S6K1 and 4E-BP1, was increased at all times during meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of PKB, an upstream kinase responsible for phosphorylating mTOR, was elevated only after 0.5 h of meal feeding for Thr(308), whereas phosphorylation Ser(473) was significantly elevated at only 0.5 and 1 h after initiation of feeding. We conclude from these studies that meal feeding stimulates two signal pathways in skeletal muscle that lead to elevated eIF4G.eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E.
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PMID:Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. 1626 69

Thiazolidinediones are a novel class of antidiabetic drugs that improve insulin sensitivity in type 2 diabetic patients. Recently, these compounds have also been shown to suppress tumor development in several animal models. The molecular basis for their antitumor action, however, is largely unknown. We report here that oral administration of thiazolidinediones (rosiglitazone and troglitazone) remarkably inhibited insulin-like growth factor-I (IGF-I)-promoted skin tumor development by 73% in BK5.IGF-1 transgenic mice, although they were previously found to be ineffective in inhibiting UV- or chemically induced mouse skin tumorigenesis. The anti-IGF-I effect of troglitazone in mouse skin keratinocytes was due to, at least partially, inhibition of IGF-I-induced phosphorylation of p70S6 kinase (p70S6K) at Thr(389), a site specifically phosphorylated by mammalian target of rapamycin (mTOR). Troglitazone did not directly inhibit mTOR kinase activity as shown by mTOR in vitro kinase assay but rapidly activated AMP-activated protein kinase (AMPK) through a yet undefined peroxisome proliferator-activated receptor gamma-independent mechanism. Expression of a dominant-negative AMPK reversed the inhibitory effect of troglitazone on IGF-I-induced phosphorylation of p70S6K, suggesting that troglitazone inhibited IGF-I and p70S6K signaling through activation of AMPK. Collectively, these data suggest that thiazolidinediones specifically inhibit IGF-I tumor-promoting activity in mouse skin through activation of AMPK and subsequent inhibition of p70S6K.
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PMID:Thiazolidinediones inhibit insulin-like growth factor-i-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity. 1645 50

The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by dexamethasone and glucagon and is completely inhibited by 100 nM insulin. Various studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin's effect. In this study we examined insulin regulation of IGFBP-1 in both subconfluent and confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic acid (100 nM) partially inhibited IGFBP-1 gene expression by 40%, but did not produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nM insulin. These results suggest a potential role for a serine/threonine phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not downstream of mTOR and is independent of Akt. In conclusion, we have found that in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is both necessary and sufficient.
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PMID:Regulation of hepatic insulin-like growth factor-binding protein-1 gene expression by insulin: central role for mammalian target of rapamycin independent of forkhead box O proteins. 1645 81

The mammalian target of rapamycin (mTOR) is a threonine kinase involved in intracellular pro-survival signaling. Its activation leads to progression from the G1 to S phase of the cell cycle. Constitutive activation of the mTOR-related messengers, including phosphatidylinositol 3-kinase, Akt kinase, ribosomal p70S6 kinase and eukaryotic translation initiation factor 4E-binding protein kinase, was found in numerous malignancies. Recent data indicate that the mTOR kinase pathway can be an attractive target for anti-cancer drug development. A well-known mTOR inhibitor is rapamycin (RAPA), previously applied as an immunosuppressive agent in transplant studies. Recently, analogs of RAPA, such as CCI-779, RAD001 and AP23573, have been developed. All of those agents are currently being tested in patients with solid or hematological tumors in several clinical trials. This review presents recent developments in targeting the mTOR kinase pathway.
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PMID:Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. 1670 4

The rapid growth of neonates is driven by high rates of skeletal muscle protein synthesis. This high rate of protein synthesis, which is induced by feeding, declines with development. Overnight-fasted 7- and 26-day-old pigs either remained fasted or were refed, and the abundance and phosphorylation of growth factor- and nutrient-induced signaling components that regulate mRNA translation initiation were measured in skeletal muscle and liver. In muscle, but not liver, the activation of inhibitors of protein synthesis, phosphatase and tensin homolog deleted on chromosome 10, protein phosphatase 2A, and tuberous sclerosis complex 1/2 increased with age. Serine/threonine phosphorylation of the insulin receptor and insulin receptor substrate-1, which downregulates insulin signaling, and the activation of AMP-activated protein kinase, an inhibitor of protein synthesis, were unaffected by age and feeding in muscle and liver. Activation of positive regulators of protein synthesis, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), and eIF4E-binding protein-1 (4E-BP1) decreased with age in muscle but not liver. Feeding enhanced mTOR, S6K1, and 4E-BP1 activation in muscle, and this response decreased with age. In liver, activation of S6K1 and 4E-BP1, but not mTOR, was increased by feeding but was unaffected by age. Raptor abundance and the association between raptor and mTOR were greater in 7- than in 26-day-old pigs. The results suggest that the developmental decline in skeletal muscle protein synthesis is due in part to developmental regulation of the activation of growth factor and nutrient-signaling components.
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PMID:Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs. 1675 50

Glutamate, the main excitatory amino acid transmitter in the vertebrate brain is involved in the dynamic changes in protein repertoire that underlie synaptic plasticity. Activity-dependent differential expression patterns occur not only in neurons but also in glial cells. In fact, a membrane to nuclei signaling has been described after ionotropic glutamate receptor stimulation in cultured chick cerebellar Bergmann glia cells. In order to characterize other levels of protein expression regulation, we explored the effect of glutamate treatment in [35S]-methionine incorporation into newly synthesized polypeptides. A time-dependent modification in protein synthesis was found. An important component of translational control is the ribosomal S6 protein kinase. Threonine phosphorylation renders the kinase active increasing translation initiation. Glutamate exposure results in ribosomal S6 protein kinase Thr389 phosphorylation in a dose and time-dependent manner that matches perfectly with the overall protein synthesis profile detected upon the excitatory amino acid. Pharmacological characterization of the receptors involved suggests the participation of both ionotropic as well as metabotropic glutamate receptors. The non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase, protein kinase B and the mammalian target of rapamycin are mediators of the glutamate effect. These results not only demonstrate that glutamate receptors activation is critically involved in translational control in glial cells adjacent to synaptic processes like cerebellar Bergmann glia cells, but also further strengthen the notion of an active participation of glial cells in synaptic transmission.
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PMID:Glutamate-dependent translational regulation in cultured Bergmann glia cells: involvement of p70S6K. 1676 30

In multicellular organisms, growth and metabolism are controlled by extracellular signals, such as insulin and insulin-like growth factors (IGFs). Depending on nutrient availability, these factors regulate cell number, cell size, storage of lipids, proteins and sugars. Here we will review recent literature on the intracellular signal transduction pathways regulating the anabolic responses in skeletal muscles. Emphasis will be put on three serine/threonine kinases, mTOR, Akt and S6 Kinase (S6K), and their role in the integration of environmental cues and the coordination of muscle growth.
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PMID:mTOR, Akt, S6 kinases and the control of skeletal muscle growth. 1677 16

Feeding promotes protein synthesis in cardiac muscle through a stimulation of the mRNA translation initiation phase of protein synthesis either secondary to nutrient-induced rises in insulin or because of direct effects of nutrients themselves. The present set of experiments establishes the effects of meal feeding on the potential signal transduction pathways that may be important in accelerating mRNA translation initiation. Hearts were obtained from male Sprague Dawley rats that had been trained to consume a meal consisting of nonpurified diet prior to, during, and following the test meal. Meal feeding raised the extent of phosphorylation of eukaryotic initiation factor (eIF)4G (Ser(1108)), which returned to basal levels within 3 h of removal of food. Likewise, meal feeding was associated with an increase in phosphorylation of eIF4E binding protein-1(4EBP1) in the gamma-form during feeding. Phosphorylation of mammalian target of rapamycin (mTOR) on Ser(2448) or Ser(2481) or 70-kDa ribosomal protein S6 kinase (S6K1) on Thr(389) was not affected by meal feeding or following removal of food. Likewise, the extent of phosphorylation of TSC2, a potential upstream regulator of mTOR, was not significantly altered during meal feeding. Phosphorylation of protein kinase B (PKB) (Thr(308)) was elevated at all time points after initiating meal feeding. Similarly, the phosphorylation of protein kinase C(PKC)-epsilon but not PKC-delta was elevated at all time points after initiating meal feeding. We conclude from these studies that meal feeding stimulates at least 2 signal pathways in cardiac muscle that raises phosphorylation of eIF4G and 4EBP1 during meal feeding and results in sustained increases in phosphorylation of PKB and PKC-epsilon.
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PMID:Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts. 1692 Aug 42

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that plays an important role in the regulation of cell proliferation and protein synthesis through the activation of its downstream target ribosomal p70 S6 kinase (p70(S6K)). The levels of p-mTOR are regulated by the protein kinase B (Akt/PKB). Therefore, the effects of insulin and rapamycin (an inhibitor of mTOR) on the phosphorylation of mTOR (Ser 2448) and p70(S6K) (Thr 389) as well as on cell proliferation in parental HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB (HepG2-CA-Akt/PKB) were studied. Insulin increased the levels of phosphorylated mTOR and p70(S6K) in both the cell lines. Rapamycin treatment partially decreased the phosphorylation of mTOR but completely abolished the phosphorylation of p70(S6K) in the absence as well as presence of insulin in both cell lines. The effect of insulin and rapamycin on the cell proliferation in both cell lines was further studied. In the presence of serum, parental HepG2 cells and HepG2-CA-Akt/PKB showed an increase in cell proliferation until 120 and 168 h respectively. Rapamycin inhibited cell proliferation under all experimental conditions more evident under serum deprived conditions. Parental HepG2 cells showed decline in the cell proliferation after 48 h and the presence of insulin prolonged cell survival until 120 h and this effect were also inhibited by rapamycin under serum deprived conditions. On the contrary, HepG2-CA-Akt/PKB cells continued proliferation until 192 h. The effects of insulin on cell proliferation were more pronounced in parental HepG2 cells as compared to HepG2-CA-Akt/PKB cells. Long term effects of rapamcyin significantly decreased the levels of p-mTOR (Ser 2448) both in the presence and absence of insulin in these cells. A positive correlation between the levels of p-mTOR (Ser2448) and cell proliferation was observed (99% confidence interval, r(2)=0.525, p<0.0001). These results suggest that rapamycin causes a decline in the cell growth through the inhibition of mTOR.
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PMID:Effects of rapamycin on cell proliferation and phosphorylation of mTOR and p70(S6K) in HepG2 and HepG2 cells overexpressing constitutively active Akt/PKB. 1695 20

Alpha4 phosphoprotein in the mTOR pathway is a prolactin (PRL)-downregulated gene product that interacts with the catalytic subunit of serine/threonine protein phosphatase 2A (PP2Ac) in rat Nb2 lymphoma cells. Transient overexpression of alpha4 in COS-1 cells inhibited PRL-inducible interferon-regulatory-1 (IRF-1) promoter activity, but the mechanism underlying this inhibition was not known. The present study showed a stable alpha4-PP2Ac complex that was not dissociated by rapamycin in COS-1 cells. Transient overexpression of alpha4 in COS-1 cells had no effect on endogenous PP2Ac protein levels but significantly increased PP2Ac carboxymethylation and PP2A activity as compared to controls. The increased PP2A activity was accompanied by decreased phosphorylation of eukaryotic initiation factor 4E-binding protein (4E-BP1) but had no effect on Stat phosphorylation. However, overexpressed alpha4 decreased arginine methylation of Stat1alpha and increased Stat1alpha binding to the Stat1alpha-specific inhibitor, PIAS1. In summary, ectopic alpha4 increased PP2A activity in COS-1 cells and this was accompanied by Stat1alpha hypomethylation and increased Stat1alpha-PIAS1 association. These events would inhibit Stat action and ultimately inhibit PRL-inducible IRF-1 promoter activity.
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PMID:Overexpression of the mTOR alpha4 phosphoprotein activates protein phosphatase 2A and increases Stat1alpha binding to PIAS1. 1708 18


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