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)

The objective of this study was to investigate the effect of insulin and IGF-I on protein synthesis and translation initiation in C2C12 myotubes in nutrient-deprived Dulbecco's phosphate buffered saline (DPBS). The results showed that insulin and IGF-I increased protein synthesis by 62% and 35% respectively in DPBS, and the effect was not affected by rapamycin, but was blocked by LY294002. Insulin and IGF-I stimulated eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP1) phosphorylation in a dose-dependent manner, and the stimulation was independent of availability of external amino acids. Both LY294002 and rapamycin blocked the insulin and IGF-I-induced increases in 4EBP1 phosphorylation. The results also showed that insulin and IGF-I were able to stimulate PKB/Akt phosphorylation, glycogen synthase kinase (GSK) 3beta phosphorylation and mTOR phosphorylation in DPBS. Insulin and IGF-I increased the amount of eIF4G associated with eIF4E in nutrient-deprived C2C12 myotubes. The amount of 4EBP1 associated with eIF4E was decreased after insulin or IGF-I stimulation. We conclude that in C2C12 myotubes, insulin and IGF-I may regulate protein synthesis and translation initiation independent of external amino acid supply via the phosphatidylinositol-3 kinase-PKB/Akt-mTOR pathway.
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PMID:Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids. 1584 20

Inhibition of p38, a member of the mitogen-activated protein kinase family, has been shown to prevent the loss of GLUT4 protein expression in insulin-resistant adipocytes without improving insulin receptor substrate 1 (IRS-1) protein levels and presumably insulin signaling. Thus, it was unclear whether p38 inhibitors would have a beneficial effect upon insulin-stimulated glucose uptake. We evaluated the effects of p38 inhibition during the development of insulin resistance upon glucose uptake and components of the insulin signaling pathway to determine the therapeutic value of p38 inhibitors. Treatment with the specific p38 inhibitor, A304000, during the development of insulin resistance increased basal glucose uptake as well as glucose uptake in response to a subsequent insulin stimulation. p38 inhibition increased GLUT1 protein levels and prevented the loss of GLUT4. However, p38 inhibition did not prevent the loss of IRS-1 protein levels or insulin signaling to PKB in insulin-resistant cells. Rapamycin, an inhibitor or mTOR, could partially improve insulin-stimulated glucose uptake through maintaining IRS-1 protein levels. Combined treatment with both A304000 and rapamycin had an additive effect upon glucose uptake. These data indicate that p38 inhibition can enhance glucose uptake through regulating the expression of GLUT1 and 4, but did not prevent the development of insulin resistance.
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PMID:Pharmacological inhibition of p38 MAP kinase results in improved glucose uptake in insulin-resistant 3T3-L1 adipocytes. 1598 98

IGF-I acutely stimulates protein synthesis in cardiac muscle through acceleration of mRNA translation. In the present study, we examined the regulatory signaling pathways and translation protein factors that potentially contribute to the myocardial responsiveness of protein synthesis to IGF-I in vivo. IGF-I was injected IV into rats and 20 min later the hearts were excised and homogenized for assay of regulatory proteins. IGF-I increased assembly of the translationally active eukaryotic initiation factor (eIF)4G.eIF4E complex. The increased assembly of eIF4G.eIF4E was associated with an enhanced eIF4G phosphorylation and increased availability of eIF4E. Increased availability of eIF4E occurred as a consequence of diminished abundance of the inactive 4E-BP1.eIF4E complex following IGF-I. The assembly of the 4E-BP1.eIF4E complex appeared to be decreased through an IGF-I-induced phosphorylation of 4E-BP1. IGF-I also caused an increase in the phosphorylation of S6K1. Activation of the potential upstream regulators of 4E-BP1 and S6K1 phosphorylation via PKB and mTOR was also observed. In contrast, there was no effect of IGF-I on phosphorylation of elongation factor (eFE)2. The results suggest the major impact of IGF-I in cardiac muscle occurred via stimulation of translation initiation rather than elongation. Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway.
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PMID:IGF-I activates the eIF4F system in cardiac muscle in vivo. 1601 Sep 89

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

Activation of the Akt/PKB protein kinase family triggers increases in cell size, metabolism and survival. Akt coordinately regulates these fundamental cellular processes through phosphorylation-dependent inactivation of tumor suppressors and activation of trophic signaling. Akt signaling stimulates transport and metabolism of both glucose and amino acids, which in turn support mTOR-dependent increases in protein translation. In addition, Akt activation directs cells to undertake a metabolic conversion from oxidative phosphorylation to aerobic glycolysis. Although this conversion promotes cell growth, it also renders cell survival dependent on a continuous supply of extracellular nutrients, which themselves are required regulatory elements in Akt signal transduction.
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PMID:Akt-dependent transformation: there is more to growth than just surviving. 1628 90

The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberin's (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangiomyomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2, focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC.
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PMID:Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. 1628 94

Autophagy is a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. A large number of intracellular/extracellular stimuli, including amino acid starvation and invasion of microorganisms, are able to induce the autophagic response in cells. The discovery of the ATG genes in yeast has greatly advanced our understanding of the molecular mechanisms participating in autophagy and the genes involved in regulating the autophagic pathway. Many yeast genes have mammalian homologs, suggesting that the basic machinery for autophagy has been evolutionarily conserved along the eukaryotic phylum. The regulation of autophagy is a very complex process. Many signaling pathways, including target of rapamycin (TOR) or mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-I (PI3K-I)/PKB, GTPases, calcium and protein synthesis all play important roles in regulating autophagy. The molecular mechanisms and regulation of autophagy are discussed in this review.
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PMID:Molecular mechanism and regulation of autophagy. 1629 39

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. Thus, inhibitors of this signaling pathway would be potential anticancer agents, particularly for cancer cells whose survival and growth are dominated by constitutively active PI3K/Akt signaling. This review describes the current understanding of small molecule drugs targeting this pathway both in vitro and in vivo. Inhibitors and functions of the upstream and downstream molecular targets of the PI3K/Akt pathway are discussed in the context of using the inhibitors to block this pathway for targeted cancer therapy. Special emphasis is placed on the following targets: receptor tyrosine kinases, PI3K, Akt, and the mammalian target of rapamycin. While the molecular therapeutic strategy holds great promise for the treatment of a variety of cancers, few small molecule inhibitors with potential high therapeutic indexes are available. Thus, new inhibitors with high selectivity, bioavailability, and potency are greatly needed. Novel approaches toward the development of PI3K/Akt pathway inhibitors as anticancer therapeutics are discussed in detail, with emphasis on chemical genetics-based and structure-based drug design.
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PMID:Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. 1630 80

The mammalian target of rapamycin (mTOR) has been identified as a growth factor and nutrient-sensitive molecule that controls the translational machinery and cell growth. Rapamycin-sensitive (RS) signaling events have also been shown to be necessary for mechanical load-induced growth of skeletal muscle, but the mechanisms involved in the mechanical activation of RS signaling are not known. The finding that mechanical stimuli induce nutrient uptake in skeletal muscle raises the possibility that mechanically induced RS signaling is mediated via a nutrient-dependent mechanism. To investigate this hypothesis, skeletal muscles (ex vivo) were stimulated with nutrients or intermittent mechanical stretch and the phosphorylation of p70S6k [P-p70(389)], PKB [P-PKB], mTOR [P-mTOR(2481)], and p38 [P-p38] was assessed. In comparison to vehicle-treated controls, both nutrient and mechanical stimuli induced P-p70(389), neither stimulus altered P-PKB or P-mTOR(2481), and only mechanical stimuli induced P-p38. The nutrient and mechanically induced increase in P-p70(389) was blocked by rapamycin, but only nutrient-induced signaling to P-p70(389) was blocked by wortmannin. Furthermore, the mechanically induced increase in P-p70(389) was not impaired by the removal of exogenous nutrients. Taken together, these results indicate that exogenous nutrients are not required for mechanically induced RS signaling and that nutrient and mechanical stimuli activate RS signaling through distinct upstream mechanisms.
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PMID:Mechanical stimuli and nutrients regulate rapamycin-sensitive signaling through distinct mechanisms in skeletal muscle. 1631 21

The present study examined the effects of an acute bout of treadmill exercise on signalling through the extracellular signal-regulated kinase (ERK)1/2 and mammalian target of rapamycin (mTOR) pathways to regulatory mechanisms involved in mRNA translation in mouse gastrocnemius muscle. Briefly, C57BL/6 male mice were run at 26 m min(-1) on a treadmill for periods of 10, 20 or 30 min, then the gastrocnemius was rapidly removed and analysed for phosphorylation and/or association of protein components of signalling pathways and mRNA translation regulatory mechanisms. Repression of global mRNA translation was suggested by disaggregation of polysomes into free ribosomes, which occurred by 10 min and was sustained throughout the time course. Exercise repressed the mTOR signalling pathway, as shown by dephosphorylation of the eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1), enhanced association of the regulatory-associated protein of mTOR with mTOR, and increased assembly of the tuberin-hamartin complex. In contrast, exercise caused no change in phosphorylation of either Akt/PKB or tuberin. Upstream of mTOR, exercise was associated with an increase in cAMP, protein kinase A activity, and AMP-activated protein kinase phosphorylation. Simultaneously, exercise caused a rapid and sustained activation of the MEK1/2-ERK1/2-p90RSK pathway, resulting in increased phosphorylation of downstream targets including eIF4E and the ribosomal protein (rp)S6 on S235/S236. Overall, the data are consistent with exercise-induced repression of mTOR signalling and global rates of mRNA translation, accompanied perhaps by up-regulated translation of selected mRNAs through regulatory mechanisms such as eIF4E and rpS6 phosphorylation, mediated by activation of the ERK1/2 pathway.
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PMID:Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. 1660 Sep 96


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