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)

The purpose of this study was to examine the role of the ribosomal protein S6 protein kinase (p70S6K), a protein synthesis regulator, in promoting retinal neuronal cell survival. Differentiated R28 rat retinal neuronal cells were used as an experimental model. Cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% newborn calf serum, and during the period of experimentation were exposed either to the absence or presence of 10 nm insulin. Insulin treatment induced p70S6K, mTOR, and Akt phosphorylation, effects that were completely prevented by the PI3K inhibitor, LY294002. Insulin-induced phosphorylation of p70S6K and mTOR was prevented by the mTOR inhibitor, rapamycin. Apoptosis, induced by serum deprivation and evaluated by Hoechst staining, was inhibited by insulin treatment in R28 cells, but not in L6 muscle cells. This effect of insulin was also largely prevented by rapamycin. Inhibition of p70S6K activity by exogenous expression of a dominant negative mutant of p70S6K prevented insulin-induced cell survival, whereas, overexpression of wild type p70S6K or expression of a rapamycin resistant form of the kinase enhanced the effect of insulin on survival. Enhanced cell survival under the latter condition was accompanied by increased p70S6K activity and phosphorylation. Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin-resistant mutant. Together, these results suggest that p70S6K plays a key role in insulin stimulated retinal neuronal cell survival.
 ...
PMID:Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. 1466 May 91

Rapamycin and its analogues have shown promising anticancer activities in preclinical and clinical studies. However, the mechanism whereby rapamycin inhibits signaling through the mammalian target of rapamycin (mTOR) remains poorly understood. Here, we show that the FKBP12/rapamycin complex is an essentially irreversible inhibitor of mTOR kinase activity in vitro. However, we observe no suppression of mTOR catalytic activity after immunoprecipitation from rapamycin-treated cells. These results suggest either that rapamycin acts as a reversible kinase inhibitor in intact cells or that the cellular effects of rapamycin are not mediated through global suppression in mTOR kinase activity. To better understand the cellular pharmacology of rapamycin, we compared the individual and combined effects of rapamycin and kinase-inactive mTOR expression on a panel of mTOR-dependent cellular responses. These studies identified glycolytic activity, amino acid transporter trafficking, and Akt kinase activity as novel, mTOR-modulated functions in mammalian cells. Whereas kinase-inactive mTOR did not enhance the decreases in cell size and glycolysis induced by rapamycin, expression of this mTOR mutant significantly enhanced the inhibitory effects of rapamycin on cell proliferation, 4EBP1 phosphorylation, and Akt activity. Unexpectedly, amino acid transporter trafficking was perturbed by kinase-inactive mTOR but not by rapamycin, indicating that this process is rapamycin insensitive. These results indicate that rapamycin exerts variable inhibitory actions on mTOR signaling functions and suggest that direct inhibitors of the mTOR kinase domain will display substantially broader anticancer activities than rapamycin.
 ...
PMID:Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. 1467 9

Current efforts in anticancer drug development are targeting key factors in cell-cycle regulation. Mammalian target of rapamycin (mTOR) is one such protein kinase that facilitates cell growth by stimulating the cell to traverse the G1 to S phase of the cell cycle. Rapamycin is the first defined inhibitor of mTOR, and the demonstration of its antitumor activity has led to great interest in this pathway as an antitumor mechanism. Analogues with better pharmacologic properties have been developed and have entered clinical trials. Human cell lines of renal cell cancer, among several other tumors, are sensitive to growth inhibition via this pathway. Ongoing clinical trials are evaluating renal cell cancer and other malignancies using therapy with mTOR inhibitors. These agents are more likely to induce growth inhibition rather than tumor regression.
 ...
PMID:Mammalian target of rapamycin (mTOR) Inhibitors. 1475 Oct 88

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.
 ...
PMID:Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. 1536 36

Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
 ...
PMID:Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. 1497 43

Cell volume changes critically determine hepatic signal transduction and metabolism. Hepatocyte swelling by insulin contributes to p38(MAPK) activation leading to inhibition of autophagic proteolysis. Recently integrins were shown to sense hypoosmotic hepatocyte swelling. Here the role of integrins, Src, and focal adhesion kinase (FAK) in insulin signaling was investigated using the intact organ model of perfused rat liver. Insulin increases [Tyr(P)(418)]Src, [Tyr(P)(397)]FAK, and dual p38(MAPK) phosphorylation by about 2-fold. Infusion of the integrin-antagonizing hexapeptide GRGDSP or the Src inhibitor PP-2 prevented activation of Src and p38(MAPK) and, consequently, proteolysis inhibition by insulin. However, insulin-induced phosphorylation of IRbeta (Tyr(1158)) and protein kinase B (PKB, Ser(473)), as well as K(+)-uptake and cell swelling, was not reduced by the inhibitors. Both hypoosmotic swelling and insulin increase the plasma membrane levels of activated beta(1) integrin. Inhibition of insulin-induced swelling by furosemide largely abolished activation of beta(1) integrin and phosphorylation of Src, but not of PKB. Rapamycin does not affect either insulin-induced K(+)-retention and cell swelling or proteolysis inhibition, indicating that swelling-dependent proteolysis inhibition occurs independently from the mammalian target of rapamycin. The data suggest that sensing of cell swelling by integrins essentially contributes to insulin signaling, thereby defining a novel way of integrin involvement in growth factor signaling.
 ...
PMID:Involvement of integrins and Src in insulin signaling toward autophagic proteolysis in rat liver. 1498 60

The effects of rapamycin on glycogen autophagy in the newborn rat liver were studied using biochemical determinations, electron microscopy, and morphometric analysis. Rapamycin increased the fractional volume of hepatocytic autophagic vacuoles, the liver lysosomal glycogen-hydrolyzing activity of acid glucosidase, the degradation of glycogen inside the autophagic vacuoles, and decreased the activity of acid mannose 6-phosphatase. These findings suggest that rapamycin, a known inhibitor of the mammalian target of rapamycin (mTOR) signaling, induces glycogen autophagy in the newborn rat hepatocytes. mTOR may participate in the regulation of this process.
 ...
PMID:Electron microscopic and biochemical study of the effects of rapamycin on glycogen autophagy in the newborn rat liver. 1498 19

In cycling cells, transcription of ribosomal RNA genes by RNA polymerase I (Pol I) is tightly coordinated with cell growth. Here, we show that the mammalian target of rapamycin (mTOR) regulates Pol I transcription by modulating the activity of TIF-IA, a regulatory factor that senses nutrient and growth-factor availability. Inhibition of mTOR signaling by rapamycin inactivates TIF-IA and impairs transcription-initiation complex formation. Moreover, rapamycin treatment leads to translocation of TIF-IA into the cytoplasm. Rapamycin-mediated inactivation of TIF-IA is caused by hypophosphorylation of Se 44 (S44) and hyperphosphorylation of Se 199 (S199). Phosphorylation at these sites affects TIF-IA activity in opposite ways, for example, phosphorylation of S44 activates and S199 inactivates TIF-IA. The results identify a new target formTOR-signaling pathways and elucidate the molecular mechanism underlying mTOR-dependent regulation of RNA synthesis.
 ...
PMID:mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. 1500 9

Insulin signaling can be negatively regulated by phosphorylation of serine 307 of the insulin receptor substrate (IRS)-1. Rapamycin, an inhibitor of the kinase mTOR, can prevent serine 307 phosphorylation and the development of insulin resistance. We further investigated the role of mTOR in regulating serine 307 phosphorylation, demonstrating that serine 307 phosphorylation in response to insulin, anisomycin, or tumor necrosis factor was quantitatively and temporally associated with activation of mTOR and could be inhibited by rapamycin. Amino acid stimulation activated mTOR and resulted in IRS-1 serine 307 phosphorylation without activating PKB or JNK. Okadaic acid, an inhibitor of the phosphatase PP2A, activated mTOR and stimulated the phosphorylation of serine 307 in a rapamycin-sensitive manner, indicating serine 307 phosphorylation requires mTOR activity but not PP2A, suggesting that mTOR itself may be responsible for phosphorylating serine 307. Finally, we demonstrated that serine 307 phosphorylated IRS-1 is detected primarily in the cytosolic fraction.
 ...
PMID:Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. 1502 Feb 50

Neointima formation, the leading cause of restenosis, is caused by proliferation of coronary artery smooth muscle cells (CASMCs) and is associated with infiltration by monocytes. Rapamycin inhibits neointima formation after stent implantation in humans. It reduces proliferation by its effects on mammalian target of rapamycin (mTOR) kinase. In this study, we investigated the expression of mTOR in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype. In neointimal CASMCs, mTOR exhibited increased phosphorylation and was translocated to the nucleus compared with control. Comparative gene expression analysis of CASMCs treated with rapamycin (100 ng/ml) revealed down-regulation of the transcription factor E2F-1, a key regulator of G(1)/S-phase entry, and of various retinoblastoma protein/E2F-1-regulated genes. In addition, we found changes in the expression of genes associated with replication, apoptosis, and extracellular matrix formation. Furthermore, rapamycin decreased the gene expression of endothelial monocyte-activating polypeptide-II (EMAP-II). This decrease of EMAP-II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells. Addition of EMAP-II counteracted the antiadhesive effect of rapamycin. Therefore, EMAP-II may comprise a mechanism of rapamycin-mediated reduction of the proinflammatory activation of CASMCs. The effects reported here of rapamycin on the down-regulation of genes involved in cell cycle progression, apoptosis, proliferation, and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation. In addition, rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC, a mechanism suggested to be mediated by the production and release of EMAP II.
 ...
PMID:Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. 1504 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>