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 immunosuppressant, rapamycin, inhibits cell growth by interfering with the function of a novel kinase, termed mammalian target of rapamycin (mTOR). The putative catalytic domain of mTOR is similar to those of mammalian and yeast phosphatidylinositol (PI) 3-kinases. This study demonstrates that mTOR is a component of a cytokine-triggered protein kinase cascade leading to the phosphorylation of the eukaryotic initiation factor-4E (eIF-4E) binding protein, PHAS-1, in activated T lymphocytes. This event promotes G1 phase progression by stimulating eIF-4E-dependent translation initiation. A mutant YAC-1 T lymphoma cell line, which was selected for resistance to the growth-inhibitory action of rapamycin, was correspondingly resistant to the suppressive effect of this drug on PHAS-1 phosphorylation. In contrast, the PI 3-kinase inhibitor, wortmannin, reduced the phosphorylation of PHAS-1 in both rapamycin-sensitive and -resistant T cells. At similar drug concentrations (0.1-1 microM), wortmannin irreversibly inhibited the serine-specific autokinase activity of mTOR. The autokinase activity of mTOR was also sensitive to the structurally distinct PI 3-kinase inhibitor, LY294002, at concentrations (1-30 microM) nearly identical to those required for inhibition of the lipid kinase activity of the mammalian p85-p110 heterodimer. These studies indicate that the signaling functions of mTOR, and potentially those of other high molecular weight PI 3-kinase homologs, are directly affected by cellular treatment with wortmannin or LY294002.
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PMID:Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. 889 71

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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PMID:8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. 1168 2

RAFT1/FRAP/mTOR is a key regulator of cell growth and division and the mammalian target of rapamycin, an immunosuppressive and anticancer drug. Rapamycin deprivation and nutrient deprivation have similar effects on the activity of S6 kinase 1 (S6K1) and 4E-BP1, two downstream effectors of RAFT1, but the relationship between nutrient- and rapamycin-sensitive pathways is unknown. Using transcriptional profiling, we show that, in human BJAB B-lymphoma cells and murine CTLL-2 T lymphocytes, rapamycin treatment affects the expression of many genes involved in nutrient and protein metabolism. The rapamycin-induced transcriptional profile is distinct from those induced by glucose, glutamine, or leucine deprivation but is most similar to that induced by amino acid deprivation. In particular, rapamycin treatment and amino acid deprivation up-regulate genes involved in nutrient catabolism and energy production and down-regulate genes participating in lipid and nucleotide synthesis and in protein synthesis, turnover, and folding. Surprisingly, however, rapamycin had effects opposite from those of amino acid starvation on the expression of a large group of genes involved in the synthesis, transport, and use of amino acids. Supported by measurements of nutrient use, the data suggest that RAFT1 is an energy and nutrient sensor and that rapamycin mimics a signal generated by the starvation of amino acids but that the signal is unlikely to be the absence of amino acids themselves. These observations underscore the importance of metabolism in controlling lymphocyte proliferation and offer a novel explanation for immunosuppression by rapamycin.
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PMID:The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. 1210 Dec 49

In this study, we observed the expression of the GSTT-1 gene in patients with myelodysplastic syndrome (MDS) at the messenger RNA level. Reverse transcription-polymerase chain reaction (RT-PCR) for GSTT-1 was performed with a pair of primers complementary to the 5' coding section and the 3' coding section of the GSTT-1 cDNA for amplifying the 623-bp band. Among 20 patients with MDS, 8 patients showed the expected 623-bp band on RT-PCR, and 12 patients showed a 500-bp band on RT-PCR, indicating that a 123-bp sequence was deleted as a mutant of the GSTT-1 gene. Furthermore, a BLAST DNA search showed that the deletion of a 123 bp sequence creates a sequence that is 63% homologous to human FKBP-rapamycin associated protein (FRAP); this protein has been termed a mammalian target of rapamycin (mTOR). We respectively transfected the wild type and the mutant type GSTT-1 gene in an expression vector to two cell lines (K562 and HL-60). The stable transformants for the wild type and the mutant type GSTT-1 genes were made by G418 selection. Interestingly, rapamycin could induce significant growth inhibition of the stable transformants for mutant type GSTT-1, which was indicative of apoptosis, but not that of those for wild type GSTT-1. These results suggest that rapamycin could be included in the therapeutic modality for the patients with MDS who have the mTOR sequences in GSTT-1 gene.
Leuk Lymphoma 2003 Jul
PMID:Mutant type glutathione S-transferase theta 1 gene homologue to mTOR in myelodysplastic syndrome: possible clinical application of rapamycin. 1291 71

A balance between survival and apoptotic signals regulates B cell development. These signals are tightly regulated by a host of molecules, including IL-7. Abnormal signaling events may lead to neoplastic transformation of progenitor B cells. Signal transduction inhibitors potentially may modulate these abnormal signals. Inhibitors of the mammalian target of rapamycin (mTOR) such as rapamycin have been used as immunosuppressive agents. We hypothesized that rapamycin might demonstrate activity against B-precursor acute lymphoblastic leukemia. We have found that rapamycin inhibited growth of B-precursor acute lymphoblastic leukemia lines in vitro, with evidence of apoptotic cell death. This growth inhibition was reversible by IL-7. One candidate as a signaling intermediate cross-regulated by rapamycin and IL-7 was p70 S6 kinase. Rapamycin also demonstrated in vivo activity in E mu-ret transgenic mice, which develop pre-B leukemia/lymphoma: E mu-ret transgenic mice with advanced disease treated daily with rapamycin as a single agent showed a >2-fold increase in length of survival as compared with symptomatic littermates who received vehicle alone. These results suggest that mammalian target of rapamycin inhibitors may be effective agents against leukemia and that one of the growth signals inhibited by this class of drugs in precursor B leukemic cells may be IL-7-mediated.
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PMID:Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. 1465 35

The protein synthetic machinery is activated by a variety of genetic alterations during tumor progression and represents an attractive target for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in regulating protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a translation repressor. It has been shown that mTOR has a direct linkage to the phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies have demonstrated that mTOR inhibition by rapamycin or its analogues have remarkable activity against a wide range of human cancers in vitro and in human tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor effect of rapamycin analogue such as CCI-779. The clinical challenge for the application of this class of anticancer drug is the ability to prospectively identify which tumors will be sensitive to mTOR inhibition. Recent studies have identified cellular markers that are associated with the in vitro activity of rapamycin or CCI-779. However, there have been no reports on how these cellular markers are expressed together in human tumor specimen. In this study, multiple components of the PI3K/PTEN-AKT-mTOR pathway were evaluated by immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor types. The results show variable expression of all the signaling proteins. For example, mTOR expression was low in brain tumors, but high in the rest of tumors. High levels of 4E-BP1 were seen in colonic adenocarcinoma and low levels in lymphoma. Phospho-AKT (p-AKT) and phospho-S6K1 (p-S6K1) were the only proteins that had significantly correlated protein expression (rs=0.51, p<0.001). Since low PTEN, high p-AKT and high p-S6K1 expression render tumors sensitive to mTOR inhibition in vitro, these criteria were used to model tumor sensitivity. Overall, 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition, with variable rates for different tumors (melanoma 0% vs ovarian 41%). This is the first report on the PI3K/PTEN-AKT-mTOR pathway in common human tumors and evaluation of the coordinated expression of different signaling proteins. This study should provide a useful tool for selecting future targeted phase II and III clinical trials in the development of this exciting class of agents.
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PMID:Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. 1501 Aug 27

Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.
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PMID:Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. 1502 79

Chronic lymphocytic B-cell leukemia (B-CLL) is an incurable disease characterized by the accumulation of monoclonal mature B cells, although disease progression relies upon cycling B-CLL cells in proliferation centers in central lymph organs. Rapamycin and its analogs are immunosuppressant drugs that exert their activity by specific inhibition of the mammalian target of rapamycin (mTOR). mTOR inhibition induces cell cycle arrest not only in normal lymphocytes but also in malignant cells. Therefore, rapamycins have recently entered the field of cancer treatment. In the present review we discuss how progression through the cell cycle is regulated in B-CLL cells and how rapamycin and its analogs can be used as target therapies against proliferating B-CLL cells. We also focus on additional effects of rapamycin, such as targeting the interaction between malignant B cells and the microenvironment.
Leuk Lymphoma 2005 Jan
PMID:Mammalian target of rapamycin (mTOR) inhibition in chronic lymphocytic B-cell leukemia: a new therapeutic option. 1562 76

Despite the great progress that has been made over the last several decades in the treatment of lymphoma, the prognosis for patients with relapsed disease, and particular sub-types of lymphoma like mantle cell and T cell lymphoma, remains quite poor. While major advances in the use of combination chemotherapy, monoclonal antibodies, peripheral blood stem cell transplants, and radioimmunotherapy, have provided new opportunities to alter the natural history of these diseases, and even improve cure rates among elected sub-populations of patients, these 'traditional' approaches have not benefited all patients, or subtypes of lymphoma. The incredibly rapid pace of understanding the molecular basis for the discrete sub-types of both non-Hodgkin's lymphoma and Hodgkin's Disease is beginning to afford exciting new opportunities to both risk stratify patients, and to identify potentially novel 'drugable' targets. These advancements in understanding the major molecular defects in lymphoma, have provided a new context in which we can rethink the use of new and old drugs, and design new ones with unique mechanisms of action. The panoply of new targets and drugs now becoming available for the treatment of lymphoma is truly daunting. A plethora of new small molecules that target bcl-2, mTOR, histone deactylases, and NF-kB have shown promising preclinical activity, and are now promising early phase activity. In many cases, the empirical observations from early clinical trials have provided invaluable clues to potentially valuable drugs like bortezomib, depsipeptide, and SAHA, These empirical observations, based on the inclusion of patients with lymphoma on these studies, have thus far proven to be as or more valuable than any other 'rational' target based approach. In addition, beyond the novel small molecules affecting unique and heretofore unrecognized biological pathways, there continues to be a robust and important effort to identify new derivatives of older generation drugs with hopefully better activity, and less toxicity. For example, new generation anthracenediones and anti-folates, and new formations of older drugs like doxorubicin, irinotecan, and vincristine afford new opportunities to favourably change the pharmacokinetic profile of these agents, and improve their overall safety profile. While it would not be possible to address each and every new such drug, we hope to touch on some of the major new themes and agents emerging for the treatment of Hodgkin's Disease and non-Hodgkin's lymphoma.
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PMID:Developing new drugs for the treatment of lymphoma. 1600 85

The mTOR alpha4 phosphoprotein is a prolactin (PRL)-downregulated gene product that is found in the nucleus of PRL-dependent rat Nb2 lymphoma cells. Alpha4 lacks a nuclear localization signal (NLS) and the mechanism of its nuclear targeting is unknown. Post-translational modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) moieties has been implicated in the nuclear transport of some proteins, including transcription factor Sp1. The nucleocytoplasmic enzymes O-beta-N-acetylglucosaminyltransferase (OGT) and O-beta-N-acetylglucosaminidase (O-GlcNAcase) adds or remove O-GlcNAc moieties, respectively. If O-GlcNac moieties contribute to the nuclear targeting of alpha4, a decrease in O-GlcNAcylation (e.g., by inhibition of OGT) may redistribute alpha4 to the cytosol. The present study showed that alpha4 and Sp1 were both O-GlcNAcylated in quiescent and PRL-treated Nb2 cells. PRL alone or PRL + streptozotocin (STZ; an O-GlcNAcase inhibitor) significantly (P <or=.05) increased the O-GlcNAc/alpha4 ratio above that in control quiescent cells. However, PRL + alloxan (ALX; an OGT inhibitor) or ALX alone did not decrease O-GlcNAcylation of alpha4 below that of controls and alpha4 remained nuclear. In comparison, PRL (+/-ALX/STZ) greatly increased Sp1 protein levels, caused a significant decrease in the GlcNAc/Sp1 ratio (P <or=0.05, n = 3) as compared to controls and partially redistributed Sp1 to the cytosol. Finally, a 50% downregulation of OGT gene expression by small interfering RNA (i.e., siOGT) partially redistributed both alpha4 and Sp1 to the cytosol. The alpha4 protein partner PP2Ac had no detectable O-GlcNAc moieties and its nuclear distribution was not affected by siOGT. In summary, alpha4 and Sp1 contained O-GlcNAc moieties, which contributed to their nuclear targeting in Nb2 cells.
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PMID:Role of O-linked beta-N-acetylglucosamine modification in the subcellular distribution of alpha4 phosphoprotein and Sp1 in rat lymphoma cells. 1605 26


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