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)

Rapamycin, a natural product inhibitor of the Raptor-mammalian target of rapamycin complex (mTORC1), is known to induce Protein kinase B (Akt/PKB) Ser-473 phosphorylation in a subset of human cancer cell lines through inactivation of S6K1, stabilization of insulin receptor substrate (IRS)-1, and increased signaling through the insulin/insulin-like growth factor-I/phosphatidylinositol 3-kinase (PI3K) axis. We report that A-443654, a potent small-molecule inhibitor of Akt serine/threonine kinases, induces Akt Ser-473 phosphorylation in all human cancer cell lines tested, including PTEN- and TSC2-deficient lines. This phenomenon is dose-dependent, manifests coincident with Akt inhibition and likely represents an alternative, rapid-feedback pathway that can be functionally dissociated from mTORC1 inhibition. Experiments performed in TSC2-/- cells indicate that TSC2 and IRS-1 cooperate with, but are dispensable for, A-443654-mediated Akt phosphorylation. This feedback event does require PI3K activity, however, as it can be inhibited by LY294002 or wortmannin. Small interfering RNA-mediated knockdown of mTOR or Rictor, components of the rapamycin-insensitive mTORC2 complex, but not the mTORC1 component Raptor, also inhibited Akt Ser-473 phosphorylation induced by A-443654. Our data thus indicate that Akt phosphorylation and activity are coupled in a manner not previously appreciated and provide a novel mode of Akt regulation that is distinct from the previously described rapamycin-induced IRS-1 stabilization mechanism.
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PMID:Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. 1733 90

Non-small cell lung cancer (NSCLC) is the commonest cause of cancer mortality worldwide. Growth factor receptor signalling pathways constitute an important mediator for tumor growth and proliferation. PTEN and pAKT play important roles in regulating signal transduction along this pathway. Separate cohorts of stage I (n=25) and stage IV (n=34) NSCLC were examined by immunohistochemistry for PTEN and pAKT expression. There was no correlation between PTEN expression and pAKT expression and neither were associated with age, sex or smoking status. Patients with stage IV disease who overexpressed pAKT (at least 2+) or were PTEN-null had poorer overall survival and progression-free survival. This suggests that PTEN-null or pAKT-positive tumors constitute more aggressive tumors whose clinical course is not altered by therapy. There was no difference in the clinical outcome for stage I disease by PTEN or pAKT expression. A greater proportion of the stage IV patients had PTEN-null disease compared to the stage I cohort, suggesting that loss of PTEN is important in the tumor biology of advanced disease. Loss of PTEN or overexpression of pAKT predicts for an aggressive subset of lung tumors that have a poor prognosis. This will allow identification of a poor prognosis subset that can be targeted with novel treatments that either restore PTEN function or target activated AKT, mTOR and other downstream signal transduction molecules.
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PMID:PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. 1734 27

Previous studies have demonstrated that the NZM2410/NZW 'z' allele of Sle1 on telomeric murine chromosome 1 led to lymphoproliferative autoimmunity, when acting in concert with the FAS(lpr) defect on the C57BL/6 background. The present report shows that the Sle1b sub-locus, harboring the NZM2410/NZW 'z' allele of SLAM, in epistasis with FAS(lpr), may be sufficient to induce lymphoproliferative autoimmunity. Disease in this simplified genetic model is accompanied by significant activation of the AKT signaling axis in both B- and T cells, as evidenced by increased phosphorylation of AKT, mTOR, 4EBP-1 and p70S6K, resulting from increased PI3K and reduced PTEN activity. In addition, blocking this axis using RAD001, an mTOR inhibitor, ameliorated lymphoproliferation and modulated serum IgG anti-nuclear auto-antibodies. Finally, mTOR inhibition also dampened signaling via parallel axes, including the MAPK and NFkB pathways. Hence, hypersignaling via the PI3K/AKT/mTOR axis appears to be an important mechanism underlying autoimmune lymphoproliferative disease, presenting itself as a potential target for therapeutic intervention.
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PMID:PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr. 1736 92

Loss of the PTEN tumor suppressor gene and amplification of the epidermal growth factor receptor (EGFR), which is common in malignant gliomas, result in activation of the mammalian target of rapamycin (mTOR). Rapamycin is a highly specific inhibitor of mTOR and induces a cytostatic effect in various glioma cell lines. DNA-damaging agents such as nitrosourea are widely used in malignant glioma treatment; therefore, we investigated the effect of rapamycin on cell growth and death in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In U251 malignant glioma (U251MG) cells, we confirmed that rapamycin enhanced ACNU-induced apoptosis. We found that rapamysin inhibited ACNU-induced p21 induction, and knocking down of p21 protein by siRNA enhanced ACNU-induced apoptosis in U251MG cells. Furthermore, adenovirus-mediated over-expression of p21 protein rescued U251MG cells from apoptosis induced by ACNU and rapamycin. Finally, treatment of intracerebral U251MG xenografts with a combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (P<0.05). These results suggest that rapamycin in combination with DNA-damaging agents may be efficacious in the treatment of malignant gliomas.
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PMID:Specific mTOR inhibitor rapamycin enhances cytotoxicity induced by alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in human U251 malignant glioma cells. 1739 Jan 4

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.
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PMID:The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. 1740 11

Hemimegalencephaly (HMEG) is a developmental brain malformation highly associated with epilepsy. Balloon cells (BCs) and cytomegalic neurons (CNs) are frequently observed in HMEG specimens. Cytomegaly in developmental brain malformations may reflect in aberrant activation of the mTOR and beta-catenin signaling cascades, known regulators of cell size. We hypothesized that there is aberrant co-expression of phospho-ribosomal S6 (P-S6) protein, a downstream effector of the mTOR cascade, as well as cyclin D1, a downstream effector of the beta-catenin pathway, in BCs and cytomegalic neurons in HMEG. We hypothesized that mutations in PTEN (a cause of HMEG associated with Proteus syndrome), TSC1 or TSC2 (tuberous sclerosis complex) genes, which are known to modulate beta-catenin and mTOR signaling could cause sporadic HMEG. Expression of cyclin D1, phospho-p70 S6 kinase (P-p70S6K, another mTOR cascade kinase), P-S6, MAP2, NeuN, or GFAP was determined by immunohistochemistry in HMEG brain tissue (n = 7 specimens). Cyclin D1, P-p70S6K, and P-S6 proteins were co-localized in BCs and CNs in the enlarged hemisphere but not in the unaffected hemisphere or in morphologically normal tissue. Cyclin D1 and P-S6 proteins were not detected in GFAP-labeled astrocytes. Sequencing of PTEN, TSC1, and TSC2 genes in cytomegalic cells co-expressing cyclin D1 and P-S6 proteins did not reveal mutations. Selective expression of cyclin D1 and P-S6 in cytomegalic cells in HMEG suggests co-activation of the beta-catenin and mTOR cascades. PTEN, TSC1, or TSC2 gene mutations were not detected suggesting that sporadic HMEG is distinct from HMEG associated with Proteus syndrome or tuberous sclerosis complex.
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PMID:Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. 1748 58

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the I kappa B kinase (IKK) pathway, associated with nuclear factor-kappaB activation, in controlling mTOR activity. The experiments show that IKK alpha controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKK beta. In these cells, IKK alpha associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKKalpha is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity.
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PMID:Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. 1761 84

In an effort to improve therapeutic options in cancer, many investigational drugs are being developed to inhibit signaling pathways that promote the survival of cancer cells. The prototypic pathway that promotes cellular survival is the phosphoinositide 3'-kinase/Akt/mammalian target of rapamycin pathway, which is constitutively activated in many types of cancers. Mechanisms for activation of the serine/threonine kinase, Akt, include loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, amplification or mutation of phosphoinositide 3'-kinase, amplification of Akt, activation of growth factor receptors and exposure to carcinogens. Activation of Akt promotes cellular survival as well as resistance to treatment with chemotherapy and/or radiation therapy. Immunohistochemical analyses have shown that Akt is activated in many types of cancers and preneoplastic lesions, and Akt activation is a poor prognostic factor in various cancers. Taken together, these data demonstrate that Akt is a valid target for inhibition. This review will focus on published data using different approaches to inhibit Akt. We will also consider how the complex regulation of the phosphoinositide 3'-kinase/Akt/mammalian target of rapamycin pathway poses practical issues concerning the design of clinical trials, potential toxicities and the likelihood of finding a therapeutic index when targeting such a critical cellular pathway.
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PMID:Targeting Akt in cancer therapy. 1766 91

Previously we reported that cadalene extracted from Zelkova serrata inhibited lung tumorigenesis in mice. However, the precise mechanism has not yet investigated. Here, we examined the effects of cadalene on signal pathways important for apoptosis, cell cycle, and protein translation in lung cancer cells. Our results showed that cadalene suppressed the expression of Akt and its phosphor-forms through controlling PI3K and PTEN. Cadalene also induced apoptosis through facilitating pro-apoptotic protein expression. In addition, cadalene caused cell cycle arrest and decreased mTOR-mediated protein translation. Taken together, cadalene may be developed as a lung cancer therapeutic agent in the future.
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PMID:Effects of 7-hydroxy-3-methoxycadalene on cell cycle, apoptosis and protein translation in A549 lung cancer cells. 1767 24

We have shown previously that blockade of epidermal growth factor receptor (EGFR) cooperates with a pan-selective inhibitor of phosphoinositide-3-kinase (PI3K) in EGFR-driven glioma. In this communication, we tested EGFR-driven glioma differing in PTEN status, treating with the EGFR inhibitor erlotinib and a novel dual inhibitor of PI3Kalpha and mTOR (PI-103). Erlotinib blocked proliferation only in PTEN(wt) cells expressing EGFR. Although erlotinib monotherapy showed little effect in PTEN(mt) glioma, PI-103 greatly augmented the antiproliferative efficacy of erlotinib in this setting. To address the importance of PI3K blockade, we showed in PTEN(mt) glioma that combining PI-103 and erlotinib was superior to either monotherapy or to therapy combining erlotinib with either rapamycin (an inhibitor of mTOR) or PIK-90 (an inhibitor of PI3Kalpha). These experiments show that a dual inhibitor of PI3Kalpha and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3Kalpha, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma.
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PMID:A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. 1780 2


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