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)

Following DNA damage, human cells arrest primarily in the G(1) and G(2) phases of the cell cycle. Here, we show that after irradiation, human cancer cells with targeted deletion of PTEN or naturally occurring PTEN mutations can exert G(1) and G(2) arrests but are unable to arrest in size. Pharmacological inhibition of phosphoinositol-3-kinase or mTOR in PTEN(-/-) cells restored the size arrest, whereas siRNA-mediated depletion of TSC2 in PTEN(+/+) cells attenuated the size arrest. Radiation treatment potentiated Akt activation in PTEN(-/-) but not PTEN(+/+) cells. Finally, abrogation of the size arrest via PTEN deletion conferred radiosensitivity both in vitro and in vivo. These results identify a new tumor suppressor gene-regulated, DNA damage-inducible arrest that occurs simultaneously with the G(1) and G(2) arrests but is genetically separable from them. We suggest that aberrant regulation of cell size during cell cycle arrest may be important in human cancer pathogenesis.
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PMID:PTEN gene targeting reveals a radiation-induced size checkpoint in human cancer cells. 1546 80

Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-B-ALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV(+)/PI(+) apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).
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PMID:Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. 1549 72

Akt, also known as protein kinase B, is a serine/threonine protein kinase with antiapoptotic activities; also, it is a downstream target of phosphatidylinositol 3-kinase. Here we show that Akt1/Akt2 play a critical role in osteoclast differentiation but not cell survival and that mammalian target of rapamycin (mTOR) and Bim, a pro-apoptotic Bcl-2 family member, are required for cell survival in isolated osteoclast precursors. To investigate the function of Akt1, Akt2, mTOR, and Bim, we employed a retroviral system for delivery of small interfering RNA into cells. Loss of Akt1 and/or Akt2 protein inhibited osteoclast differentiation due to down-regulation of IkappaB-kinase (IKK) alpha/beta activity, phosphorylation of IkappaB-alpha, nuclear translocation of nuclear factor-kappaB (NFkappaB) p50, and NFkappaB p50 DNA-binding activity. Surprisingly, deletion of Akt1 and/or Akt2 protein did not stimulate cleaved caspase-3 activity and failed to promote apoptosis. Conversely, loss of mTOR protein induced apoptosis due to up-regulation of cleaved caspase-3 activity. In addition, we found that mTOR is downstream of phosphatidylinositol 3-kinase (but not Akt) and that macrophage colony-stimulating factor regulates Bim expression through mTOR activation for cell survival. These results demonstrate that Akt1/Akt2 are key elements in osteoclast differentiation and that the macrophage colony-stimulating factor stimulation of mTOR leading to Bim inhibition is essential for cell survival in isolated osteoclast precursors.
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PMID:Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. 1554 69

Mammalian target of rapamycin (mTOR) is a protein kinase that integrates signals from mitogens and the nutrients, glucose and amino acids, to regulate cellular growth and proliferation. Previous findings demonstrated that glucose robustly activates mTOR in an amino acid-dependent manner in rodent and human islets. Furthermore, activation of mTOR by glucose significantly increases rodent islet DNA synthesis that is abolished by rapamycin. Glucagon-like peptide-1 (GLP-1) agonists, through the production of cAMP, have been shown to enhance glucose-dependent proinsulin biosynthesis and secretion and to stimulate cellular growth and proliferation. The objective of this study was to determine if the glucose-dependent and cAMP-mediated mechanism by which GLP-1 agonists enhance beta-cell growth and proliferation is mediated, in part, through mTOR. Our studies demonstrated that forskolin-generated cAMP resulted in activation of mTOR at basal glucose concentrations as assessed by phosphorylation of S6K1, a downstream effector of mTOR. Conversely, an adenylyl cyclase inhibitor partially blocked glucose-induced S6K1 phosphorylation. Furthermore, the GLP-1 receptor agonist, Exenatide, dose-dependently enhanced phosphorylation of S6K1 at an intermediate glucose concentration (8 mmol/l) in a rapamycin-sensitive manner. To determine the mechanism responsible for this potentiation of mTOR, the effects of intra- and extracellular Ca2+ were examined. Glyburide, an inhibitor of ATP-sensitive K+ channels (K(ATP) channels), provided partial activation of mTOR at basal glucose concentrations due to the influx of extracellular Ca2+, and diazoxide, an activator of KATP channels, resulted in partial inhibition of S6K1 phosphorylation by 20 mmol/l glucose. Furthermore, Exenatide or forskolin reversed the inhibition by diazoxide, probably through mobilization of intracellular Ca2+ stores by cAMP. BAPTA, a chelator of intracellular Ca2+, resulted in inhibition of glucose-stimulated S6K1 phosphorylation due to a reduction in cytosolic Ca2+ concentrations. Selective blockade of glucose-stimulated Ca2+ influx unmasked a protein kinase A (PKA)-sensitive component involved in the mobilization of intracellular Ca2+ stores, as revealed with the PKA inhibitor H-89. Overall, these studies support our hypothesis that incretin-derived cAMP participates in the metabolic activation of mTOR by mobilizing intracellular Ca2+ stores that upregulate mitochondrial dehydrogenases and result in enhanced ATP production. ATP can then modulate KATP channels, serve as a substrate for adenylyl cyclase, and possibly directly regulate mTOR activation.
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PMID:Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. 1556 16

Fetal growth retardation, a common end point for a variety of conditions affecting mother and fetus, is associated with reduced liver mass. We have performed studies to determine the mechanism for decreased liver mass in a maternal starvation model of fetal growth restriction in the rat. Pregnant dams were deprived of food for 48 h before delivery on embryonic day 19 (E19). Fetal body weight was not affected. However, fetal liver weight was reduced by approximately 15%. Immunostaining of fetal liver for proliferating cell nuclear antigen and flow cytometry on isolated fetal hepatocytes showed G1 cell cycle arrest in samples from starved dams. Based on our prior studies showing attenuated hepatic insulin signaling in the late gestation fetal rat, we tested the hypothesis that G1 arrest in our model might be due to altered nutrient signaling. Fetal plasma amino acid analyses showed no decrease in branched-chain amino acids, but arginine concentrations were decreased in fetuses of fasted mothers. Reduced arginine in E19 fetal hepatocyte culture media was associated with decreased DNA synthesis. Whereas levels of cyclins D and E were unchanged in fetal hepatocytes exposed to low arginine, cyclin E-dependent kinase activity was reduced. Low arginine also induced changes in the translational machinery, indicative of impaired signaling through the nutrient sensing kinase mammalian target of rapamycin. Our results are consistent with the hypothesis that restricted nutrient availability signals to the hepatocyte cell cycle in fetuses of fasted mothers, thereby accounting for decreased hepatocyte proliferation and liver mass.
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PMID:Effects of maternal starvation on hepatocyte proliferation in the late gestation fetal rat. 1561 45

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to have anticancer effects in many models. We have investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, while mRNA levels were unchanged. Furthermore, pravastatin was found to induce phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to active Mdm2 and has been shown to increase its ubiquitin ligase activity and lead to increased p53 degradation. Our data show that statins attenuated the p53 response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil and benzo(a)pyrene. Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 degradation. The induction of p53 responsive genes and apoptosis was attenuated. Mdm2 and p53 were also studied in vivo in rat liver employing immunohistochemistry, and it was found that constitutive Mdm2 expression was changed in livers of pravastatin-treated rats. We also show that the p53 response to a challenging dose of diethylnitrosamine was attenuated in hepatocytes in situ and in primary cultures of hepatocytes by pravastatin pretreatment. Taken together, these data indicate that statins induce an mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the duration and intensity of the p53 response to DNA damage in hepatocytes.
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PMID:HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage. 1562 77

Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.
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PMID:Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. 1577 87

Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.
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PMID:The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. 1579 77

Growth factors are polypeptides that combine with specific membrane receptors on animal cells to stimulate proliferation, but they also stimulate glucose transport, uridine phosphorylation, intermediary metabolism, protein synthesis, and other processes of the coordinate response. There are a variety of nonspecific surface action treatments which stimulate the same set of reactions as the growth factors do, of which protein synthesis is most directly related to the onset of DNA synthesis. Mg(2+) is required for a very wide range of cellular reactions, including all phosphoryl transfers, and its deprivation inhibits all components of the coordinate response that have so far been tested. Growth factors raise the level of free Mg(2+) closer to the optimum for the initiation of protein synthesis. The resulting increase in protein synthesis accelerates progression through G1 to the onset of DNA synthesis and mitosis. None of the other 3 major cellular cations are similarly involved in growth regulation, although internal pH may play an auxiliary role. Almost 10(5) externally bound divalent cations are displaced from membranes for every attached insulin molecule, implying a conformational membrane change that releases enough Mg(2+) from the internal surface of the plasma membrane to account for the increase in free cytosolic Mg(2+). It is proposed that mTOR, the central control point for protein synthesis of the PI 3-K kinase cascade stimulated by insulin, is regulated by MgATP(2-) which varies directly with cytosolic Mg(2+). Other elements of the coordinate response to growth factors such as the increased transport of glucose and phosphorylation of uridine are also dependent upon an increase of Mg(2+). Deprivation of Mg(2+) in neoplastically transformed cultures normalizes their appearance and growth behavior and raises their abnormally low Ca(2+) concentration. Tight packing of the transformed cells at very high saturation density confers the same normalizing effects, which are retained for a few days after subculture at low density. The results suggest that the activity of Mg(2+) within the cell is a central regulator of normal cell growth, and the loss of its membrane-mediated control can account for the neoplastic phenotype.
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PMID:Central roles of Mg2+ and MgATP2- in the regulation of protein synthesis and cell proliferation: significance for neoplastic transformation. 1579 43

Control of translation initiation is one means by which cells regulate growth and proliferation, with components of the protein-synthesizing machinery having oncogenic potential. Expression of latency protein LMP2A by the human tumor virus Epstein-Barr virus (EBV) activates phosphatidylinositol 3-kinase/Akt located upstream of an essential mediator of growth signals, mTOR (mammalian target of rapamycin). We show that mTOR is activated by expression of LMP2A in carcinoma cells, leading to wortmannin- and rapamycin-sensitive inhibition of the negative regulator of translation, eukaryotic initiation factor 4E-binding protein 1, and increased c-Myc protein translation. Intervention by this DNA tumor virus in cellular translational controls is likely to be an integral component of EBV tumorigenesis.
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PMID:Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A. 1582 64


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