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)

Prolonged exposure of 3T3-L1 adipocytes to insulin increases GLUT1 protein content while diminishing GLUT4. These changes arise in part from changes in mRNA transcription. Here we examined whether there are also specific effects of insulin on GLUT1 and GLUT4 mRNA translation. Insulin enhanced association of GLUT1 mRNA with polyribosomes and decreased association with monosomes, suggesting increased translation. Conversely, insulin arrested the majority of GLUT4 transcripts in monosomes. Insulin inactivates the translational suppressor eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) through the mammalian target of rapamycin (mTOR). Hence, we examined the effect of rapamycin on GLUT1 mRNA translation and protein expression. Rapamycin abrogated the insulin-mediated increase in GLUT1 protein synthesis through partial inhibition of GLUT1 mRNA translation and partial inhibition of the rise in GLUT1 mRNA. 4E-BP1 inhibited GLUT1 mRNA translation in vitro. Because phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), in concert with mTOR, inactivate 4E-BP1, we explored their role in GLUT1 protein expression. Cotransfection of cytomegalovirus promoter-driven, hemagglutinin epitope-tagged GLUT1 with dominant inhibitory mutants of PI3K or PKB inhibited the insulin-elicited increase in hemagglutinin-tagged GLUT1 protein. These results unravel the opposite effects of insulin on GLUT1 and GLUT4 mRNA translation. Increased GLUT1 mRNA translation appears to occur via the PI3K/PKB/mTOR/4E-BP1 cascade.
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PMID:Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. Role of mammalian target of rapamycin, protein kinase b, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation. 1055 78

Signaling mediated by the cellular kinase mammalian target of rapamycin (mTOR) activates cap-dependent translation under normal (nonstressed) conditions. However, translation is inhibited by cellular stress responses or rapamycin treatment, which inhibit mTOR kinase activity. We show that during human cytomegalovirus (HCMV) infection, viral protein synthesis and virus production proceed relatively normally when mTOR kinase activity is inhibited due to hypoxic stress or rapamycin treatment. Using rapamycin inhibition of mTOR, we show that HCMV infection induces phosphorylation of two mTOR effectors, eucaryotic initiation factor 4E (eIF4E) binding protein (4E-BP) and eIF4G. The virally induced phosphorylation of eIF4G is both mTOR and phosphatidylinositol 3-kinase (PI3K) independent, whereas the phosphorylation of 4E-BP is mTOR independent, but PI3K dependent. HCMV infection does not induce mTOR-independent phosphorylation of a third mTOR effector, p70S6 kinase (p70S6K). We show that the HCMV-induced phosphorylation of eIF4G and 4E-BP correlates with the association of eIF4E, the cap binding protein, with eIF4G in the eIF4F translation initiation complex. Thus, HCMV induces mechanisms to maintain the integrity of the eIF4F complex even when mTOR signaling is inhibited.
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PMID:Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase. 1545 23

mTOR is a downstream effector of phosphatidylinositol-3-kinase pathway, which is involved in the regulation of protein synthesis and interacts with cell cycle progression. Sirolimus and everolimus may interfere with mTOR activity after their binding with FK binding protein. These drugs may prevent rejection of organ transplants by inhibiting the proliferation signals provided by interleukins 2 and 15, so causing lymphocyte cycle arrest in the G1 phase. Experimental studies have also shown that some oncoproteins may derive either from an overactivity of phosphatidylinositol-3-kinase or from a loss of the tumor suppressor PTEN. As mTOR is an important mediator of the kinase cascade and may also be antiangiogenic, it has become an attractive target in some malignancies. In organ transplant recipients some retrospective studies have shown that patients treated with mTOR inhibitors for immunosuppression had a reduced incidence of neoplasia in comparison with patients treated with calcineurin inhibitors. mTOR is also involved in the replication of cytomegalovirus in the host cells, as it favors transcription and translation signals necessary for virus replication. Recent studies reported a very low incidence of cytomegalovirus infection in organ transplant patients treated wih either sirolimus or everolimus. Finally, mTOR inhibitors may offer vascular protection, as they mediate vascular endothelial growth factor. In cardiac transplants treated with everolimus, cyclosporine, and steroids the average increase in maximal intimal thickness and the incidence of vasculopathy were significantly lower than in patients treated with azathioprine, cyclosporine, and steroids.
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PMID:The pleiotropic effects of mTor inhibitors. 1559 48

Calcineurin inhibitors (CNI) have played an important role in improving graft survival. However, the balance between preventing immunologic allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. There are three major CNI-sparing strategies. CNI MINIMIZATION: The advent of mycophenolate mofetil (MMF) allows cyclosporine (CsA) reduction to ameliorate renal function in patients with chronic renal allograft dysfunction, without increasing acute rejection rates. In combination with mTOR inhibitors, very low CNI levels may be sufficient to prevent acute rejection. However, in this association, CNI nephrotoxicity is magnified by pharmacokinetic interaction. CNI WITHDRAWAL: CNI withdrawal has been attempted in regimens containing MMF or sirolimus (SRL). Introduction of MMF in patients with chronic allograft nephropathy (CAN) followed by CNI withdrawal resulted in stabilization or improvement of renal function and hypertension profile, although there is some risk of acute rejection. In regimes based on SRL, CNI withdrawal is a safety strategy, achieving a sustained improvement of renal function, histology, and graft survival. There is not consensus at all whether MMF should be added or not in patients converted from CNI to mTOR inhibitor. CNI AVOIDANCE: Polyclonal-based regimens with MMF and steroids have shown acceptable acute rejection rates, but high rates of cytomegalovirus (CMV) and opportunistic infections. Conversely, anti-IL-2R in combination with MMF and steroids resulted in 50% incidence of acute rejection, thus suggesting that CNI avoidance is not feasible in a regimen based on MMF. Alternatively, a protocol based on anti-IL-2R induction therapy combined with SRL, MMF, and prednisone has shown an efficient prevention of acute rejection, higher creatinine clearance and lower rate of CAN in comparison with a group treated with CNI. New strategies using costimulation blockade may help in the development of safe CNI-free regimens. In summary, in renal transplantation the new immunosuppressive medications have made feasible old aspirations such as minimization, withdrawal, or even avoidance of CNI.
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PMID:Calcineurin-inhibitor-sparing immunosuppressive protocols. 1638 20

We have constructed an oncolytic adenovirus expressing the Escherichia coli nitroreductase gene nfsB from an internal ribosome entry site (IRES) in the adenovirus L5 major late transcript. The virus (Tcf-NTR) has Tcf transcription factor-binding sites in the E1A, E1B, and E4 promoters, which restrict viral replication to cells that have activation of the Wnt signaling pathway. This virus was compared with an E1B-55K-deleted virus expressing nitroreductase (NTR) from a cytomegalovirus (CMV) promoter in the E1B-55K region [CRAd-NTR(PS1217H6)]. Both viruses express NTR in colorectal cancer cell lines and show increased cytopathic effect in the presence of the prodrug CB1954. Unlike the Tcf-NTR virus, the CMV-NTR virus expresses NTR in human lung fibroblasts and sensitizes these normal cells to CB1954. The in vivo activity of the viruses was tested in SW620 xenografts in nude mice by intravenous injection of 1,011 particles of virus followed 1 week later by intraperitoneal injections of CB1954. The CMV-NTR virus produced minimal effects in this model. The median time to form 1,000-mm(3) tumors in mice treated with the Tcf-NTR virus plus CB1954 was increased from 14 to 26 days (p=0.003), but this was due mainly to the direct oncolytic effect of the virus. Combination therapy with 3 x 10(11) particles of Tcf-NTR virus (given intravenously) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) (given orally) significantly improved survival (median, >50 days), and addition of CB1954 to this regimen further delayed tumor growth. These results show that the Tcf-NTR virus is more tumor selective and active than the CMV-NTR virus. At the level of transduction that can be achieved currently with oncolytic viruses given intravenously, drugs such as RAD001, which do not require activation by the virus, produce greater increases in efficacy than prodrugs such as CB1954.
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PMID:Late expression of nitroreductase in an oncolytic adenovirus sensitizes colon cancer cells to the prodrug CB1954. 1639 Feb 78

Everolimus (Certican) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers.
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PMID:Everolimus: a review of its use in renal and cardiac transplantation. 1659 67

Signaling mediated by the mammalian target of rapamycin kinase (mTOR) is activated during human cytomegalovirus (HCMV) infection. mTOR is found in two complexes differing by the binding partner, rictor or raptor. Activated mTOR-raptor promotes cap-dependent translation through the hyperphosphorylation of the eIF4E-binding protein (4E-BP). This activity of the raptor complex is normally inhibited by cell stress responses or the drug rapamycin. However, we previously showed that this inhibition of mTOR signaling can be circumvented during HCMV infection such that hyperphosphorylation of 4E-BP is maintained. Here we show that HCMV infection also activates the rictor complex, as indicated by increased phosphorylation of Akt S473; this phosphorylation is insensitive to rapamycin but sensitive to caffeine in both uninfected and infected cells. By using short-hairpin RNAs to deplete rictor and raptor, we find that rictor is more significant than raptor for the viral infection. Surprisingly, the inhibitory effects of rapamycin on viral growth are primarily due to the presence of rictor, not raptor. Raptor and rictor depletion experiments show that in HCMV-infected cells, both raptor- and rictor-containing complexes can mediate the hyperphosphorylation of 4E-BP and the phosphorylation of p70S6 kinase. Under these conditions, the rictor complex is rapamycin-sensitive for the hyperphosphorylation of 4E-BP, but the raptor complex is not. These data suggest that, during HCMV infection, the rictor- and raptor-containing complexes are modified such that their substrate specificities and rapamycin sensitivities are altered. Our data also suggest that the present understanding of rapamycin's inhibitory effects is incomplete.
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PMID:Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. 1695 81

Human cytomegalovirus (HCMV) infection increases synthetic rates in infected cells. The resulting increase in energy utilization could potentially increase the AMP:ATP ratio, causing activation of 5'-AMP-activated protein kinase (AMPK). Activated AMPK promotes inhibition of mammalian target of rapamycin (mTOR) kinase, which could be deleterious to the viral infection. Using the AMPK-activating drug 5-amino-4-imidazolecarboxamide ribose (AICAR), we showed that, by 12 h post-HCMV infection, inhibition of mTOR by AMPK is circumvented. However, growth curves showed that progeny virion production is inhibited when AICAR is added, suggesting other inhibitory effects of AICAR or activated AMPK.
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PMID:AMPK-mediated inhibition of mTOR kinase is circumvented during immediate-early times of human cytomegalovirus infection. 1721 82

The most frequent causes of late kidney allograft failure are chronic rejection, nonalloimmune injury and death, all of which may depend on the characteristics of the donor and recipient, but may also be influenced by the type of immunosuppression. Combining calcineurin inhibitors (CNIs) and corticosteroids offers potent immunosuppression, but may also cause side effects leading to progressive graft dysfunction or an increased risk of death. New immunosuppressive strategies may come from the availability of inhibitors of mTOR, a downstream effector of phosphatidylinositol-3 kinase that provides the signal for cell proliferation by phosphorylating a cascade of kinases. Recent trials have shown that it is possible to minimize the dose or withdraw CNIs a few weeks after transplantation when they are combined with mTOR inhibitors and their combination may also make it possible to minimize or avoid the use of corticosteroids. Moreover, by inhibiting the signal for cell proliferation, mTOR inhibitors may reduce the replication of cytomegalovirus inside host cells, prevent transplant vasculopathy, and exert anti-oncogenic activity. All of these characteristics offer a ray of hope for reducing the risk of long-term allograft failure.
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PMID:Can mTOR inhibitors reduce the risk of late kidney allograft failure? 1763 37

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that remains the major infectious cause of birth defects, as well as being an important opportunistic pathogen. Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved process responsible for the degradation of cytoplasmic macromolecules, and the elimination of damaged organelles via a lysosomal pathway. This process is also triggered in organisms by stressful conditions and by certain diseases. Previous observations have suggested that autophagy (also known as xenophagy in this case) may contribute to innate immunity against viral infections. Recent studies on HSV-1, another herpesvirus, have shown that HSV-1 is able to avoid this cellular defense by means of a viral protein, ICP34.5, which antagonizes the host autophagy response. However, it was not known whether HCMV was also able to counteract autophagy. Here, we show that HCMV infection drastically inhibits autophagosome formation in primary human fibroblasts. Autophagy was assessed by GFP-LC3 redistribution, LC3-II and p62 accumulation and electron microscopy. Inhibition of autophagy occurred early in the infection by a mechanism involving viral protein(s). Indeed, only infected cells expressing viral proteins displayed a striking decrease of autophagy; whereas bystander, non-infected cells displayed a level of autophagy similar to that of control cells. HCMV activated the mTOR signaling pathway, and rendered infected cells resistant to rapamycin-induced autophagy. Moreover, infected cells also became resistant to the stimulation of autophagy by lithium chloride, an mTOR-independent inducer of autophagy. These findings suggest that HCMV has developed efficient strategies for blocking the induction of autophagy during infection.
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PMID:Human cytomegalovirus controls a new autophagy-dependent cellular antiviral defense mechanism. 1834 Jan 11


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