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 precise mechanisms by which imatinib mesylate (STI571) and interferon alpha (IFNalpha) exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL-expressing cells. Treatment of IFN-sensitive KT-1 cells with IFNalpha resulted in phosphorylation/activation of mammalian target of rapamycin (mTOR) and downstream activation of p70 S6 kinase. The IFN-activated p70 S6 kinase was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5'-untranslated region. In addition, IFNalpha treatment resulted in an mTOR- and/or phosphatidyl-inositol 3'(PI 3') kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its deactivation and dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. In contrast to the effects of IFNs, imatinib mesylate suppressed p70 S6 kinase activity, consistent with inhibition of BCR-ABL-mediated activation of the mTOR/p70 S6 kinase pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of imatinib mesylate on primary leukemic granulocyte macrophage-colony-forming unit (CFU-GM) progenitors from patients with chronic myelogenous leukemia (CML). Taken altogether, our data demonstrate that IFNs and imatinib mesylate differentially regulate PI 3' kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of imatinib mesylate with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML.
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PMID:Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. 1579 Jul 87

The phosphatidyl-inositol 3 kinase (PI3k)/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in nonresponder samples. Anthracyclines activate nuclear factor kappaB (NF-kappaB), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-kappaB in ALL samples. Using a short interfering (si) RNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-kappaB activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-kappaB was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts--PI3k/Akt through the mammalian target of rapamycin and NF-kappaB through FKBP51--suggesting that the drug could be beneficial in the treatment of childhood ALL.
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PMID:Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. 1587 82

Phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappaB) signaling pathways play a critical role in mediating survival signals. In this study we have investigated how loss of dystrophin (the primary cause of Duchenne muscular dystrophy) modulates the activation of PI3K/Akt and NF-kappaB signaling pathways in skeletal muscle in response to mechanical stimulation. Activation of Akt was significantly higher in diaphragm muscle from dystrophin-deficient mdx mice compared to normal mice at both prenecrotic and necrotic states. Higher activation of Akt was also observed in cultured dystrophin-deficient primary myotubes differentiated in vitro. Application of passive mechanical stretch ex vivo synergistically increased the activation of Akt in diaphragm of mdx mice. Stretch-induced activation of PDK-1 and PI3K were also higher in diaphragm of mdx mice compared to normal mice. Pretreatment of diaphragm with PI3K inhibitor LY294002 blocked the activation of Akt in normal and mdx mice. Higher activation of Akt was associated with increased phosphorylation of its downstream targets glycogen synthase kinase 3beta (GSK3beta), FKHR, and mammalian target of rapamycin (mTOR). Treatment of diaphragm muscle with LY294002 inhibited the stretch-induced activation of IkappaB (IkappaB) kinase (IKK) and NF-kappaB transcription factor in normal and mdx mice. Mechanical stretch also reduced the interaction of HDAC1 with RelA subunit of NF-kappaB in diaphragm muscle. Finally, cellular levels of Bcl-2, cIAP1, and integrin beta1 and activation of integrin linked kinase were higher in diaphragm muscle of mdx mice compared to normal mice. Taken together, our data suggest that loss of dystrophin and/or mechanical stretch results in the up-regulation of P13K/Akt and NF-kappaB signaling pathways in skeletal muscle.
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PMID:Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch. 1674 26

Phosphatidylinositol 3-kinase-related kinases (PIKKs) consisting of SMG-1, ATM, ATR, DNA-PKcs, and mTOR are a family of proteins involved in the surveillance of gene expression in eukaryotic cells. They are involved in mechanisms responsible for genome stability, mRNA quality, and translation. They share a large N-terminal domain and a C-terminal FATC domain in addition to the unique serine/threonine protein kinase (PIKK) domain that is different from classical protein kinases. However, structure-function relationships of PIKKs remain unclear. Here we have focused on one of the PIKK members, SMG-1, which is involved in RNA surveillance, termed nonsense-mediated mRNA decay (NMD), to analyze the roles of conserved and SMG-1-specific sequences on the intrinsic kinase activity. Analyses of sets of point and deletion mutants of SMG-1 in a purified system and intact cells revealed that the long N-terminal region and the conserved leucine in the FATC domain were essential for SMG-1 kinase activity. However, the conserved tryptophan in the TOR SMG-1 (TS) homology domain and the FATC domain was not. In addition, the long insertion region between PIKK and FATC domains was not essential for SMG-1 kinase activity. These results indicated an unexpected feature of SMG-1, i.e. that distantly located N- and C-terminal sequences were essential for the intrinsic kinase activity.
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PMID:Distant N- and C-terminal domains are required for intrinsic kinase activity of SMG-1, a critical component of nonsense-mediated mRNA decay. 1722 28

Programmed cell death-4 (PDCD4) is a recently discovered tumor suppressor protein that inhibits protein synthesis by suppression of translation initiation. We investigated the role and the regulation of PDCD4 in the terminal differentiation of acute myeloid leukemia (AML) cells. Expression of PDCD4 was markedly up-regulated during all-trans retinoic acid (ATRA)-induced granulocytic differentiation in NB4 and HL60 AML cell lines and in primary human promyelocytic leukemia (AML-M3) and CD34(+) hematopoietic progenitor cells but not in differentiation-resistant NB4.R1 and HL60R cells. Induction of PDCD4 expression was associated with nuclear translocation of PDCD4 in NB4 cells undergoing granulocytic differentiation but not in NB4.R1 cells. Other granulocytic differentiation inducers such as DMSO and arsenic trioxide also induced PDCD4 expression in NB4 cells. In contrast, PDCD4 was not up-regulated during monocytic/macrophagic differentiation induced by 1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl-phorbol-13-acetate in NB4 cells or by ATRA in THP1 myelomonoblastic cells. Knockdown of PDCD4 by RNA interference (siRNA) inhibited ATRA-induced granulocytic differentiation and reduced expression of key proteins known to be regulated by ATRA, including p27(Kip1) and DAP5/p97, and induced c-myc and Wilms' tumor 1, but did not alter expression of c-jun, p21(Waf1/Cip1), and tissue transglutaminase (TG2). Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was found to regulate PDCD4 expression because inhibition of PI3K by LY294002 and wortmannin or of mTOR by rapamycin induced PDCD4 protein and mRNA expression. In conclusion, our data suggest that PDCD4 expression contributes to ATRA-induced granulocytic but not monocytic/macrophagic differentiation. The PI3K/Akt/mTOR pathway constitutively represses PDCD4 expression in AML, and ATRA induces PDCD4 through inhibition of this pathway.
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PMID:Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. 1725 49

Coordination of cell death and survival is crucial during embryogenesis and adulthood, and alteration of this balance can result in degeneration or cancer. Growth factor receptors such as Met can activate phosphatidyl-inositol-3' kinase (PI3K), a major intracellular mediator of growth and survival. PI3K can then antagonize p53-triggered cell death, but the underlying mechanisms are not fully understood. We used genetic and pharmacological approaches to uncover Met-triggered signaling pathways that regulate hepatocyte survival during embryogenesis. Here, we show that PI3K acts via mTOR (Frap1) to regulate p53 activity both in vitro and in vivo. mTOR inhibits p53 by promoting the translation of Mdm2, a negative regulator of p53. We also demonstrate that the PI3K effector Akt is required for Met-triggered Mdm2 upregulation, in addition to being necessary for the nuclear translocation of Mdm2. Inhibition of either mTOR or Mdm2 is sufficient to block cell survival induced by Hgf-Met in vitro. Moreover, in vivo inhibition of mTOR downregulates Mdm2 protein levels and induces p53-dependent apoptosis. Our studies identify a novel mechanism for Met-triggered cell survival during embryogenesis, involving translational regulation of Mdm2 by mTOR. Moreover, they reinforce mTOR as a potential drug target in cancer.
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PMID:Met acts on Mdm2 via mTOR to signal cell survival during development. 1732 61

Phosphatidylinositol 3-kinases (PI3Ks) constitute important regulators of signaling pathways. The PIK3CA gene encoding the p110-alpha catalytic subunit represents one of the highly mutated oncogenes identified in human cancer. Here, we report new markers for in vivo PI3K activation in prostate. To that end, we used a transgenic mouse line, which expresses a constitutively active p110-alpha subunit in the epithelial cells of the prostate. The activity of the PI3K pathway in the prostate was proven by assessing the phosphorylation of the PI3K direct target AKT1 and of the mTOR target eukaryotic translation initiation factor 4G (eIF4G). To establish also transcriptional ('late') targets of the PI3K pathway, we tested two genes, Mst1 and RanBP2, which we recently described as transcriptional targets of the growth factor platelet-derived growth factor-beta. We show that the levels of both proteins are elevated in transgenic animals. Additionally, we describe that the phosphorylation of AKT and eIF4G, as well as the elevation of the Mst1 and RanBP2 protein levels, can be inhibited in vivo in transgenic animals by the PI3K inhibitor LY294002. Finally, we performed human tissue microarray experiments with the four markers. Since they define overlapping but not identical subsets of the tested tissue panel, a combination of all four markers might lead to a more accurate diagnosis of the status of the PI3K-signaling cascade in cancer patients.
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PMID:Mst1, RanBP2 and eIF4G are new markers for in vivo PI3K activation in murine and human prostate. 1737 72

Phosphatidylinositol 3-kinase (PI3K) signalling plays a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation, and tumourigenesis. PI3K is overexpressed in many human cancers, including endometrial carcinomas, one of the most common female genital tract malignancies. Here, we used small interfering RNA (siRNA) targeted to PI3K p110-beta to determine whether inhibition of the beta isoform could be a potential therapeutic target for endometrial carcinoma. In this study, treatment of HEC-1B endometrial cancer cells with PI3K p110-beta-specific siRNA resulted in increased apoptosis and decreased tumour cell proliferation. Depletion of PI3K p110-beta decreased the protein levels of AKT1, AKT2, pAKT, and mTOR-downstream targets of PI3K. Knock-down of PI3K p110-beta by siRNA also induced decreased expression of cyclin E and Bcl-2, suggesting that PI3K p110-beta stimulates tumour growth, at least in part by regulating cyclin E and Bcl-2. Thus, our results indicate that siRNA-mediated gene silencing of PI3K p110-beta may be a useful therapeutic strategy for endometrial cancers overexpressing PI3K p110-beta.
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PMID:Targeted RNA interference of phosphatidylinositol 3-kinase p110-beta induces apoptosis and proliferation arrest in endometrial carcinoma cells. 1742 68

Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition with imatinib, yet will eventually exhibit resistance. Imatinib-resistance mechanisms are heterogeneous, and little is known about KIT functional roles in imatinib-resistant GIST. Biological consequences of biochemical inhibition of KIT, phosphatidyl-inositol-3-kinase (PI3-K), PLCgamma, MAPK/ERK kinase/mitogen-activated protein kinase (MEK/MAPK), mammalian target of rapamycin (mTOR) and JAK were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays in GIST cell lines from imatinib-sensitive GIST (GIST882), imatinib-resistant GISTs (GIST430 and GIST48) and KIT-negative GIST (GIST62). KIT activation was 3- to 6-fold higher in GIST430 and GIST48 than in GIST882, whereas total KIT expression was comparable in these three GIST lines. In addition to the higher set point for KIT activation, GIST430 and GIST48 had intrinsic imatinib resistance. After treatment with 1 muM imatinib, residual KIT activation was 6- and 2.8-fold higher in GIST430 and GIST48, respectively, compared to GIST882. In all GIST lines, cell growth arrest resulted from PI3-K inhibition, and - to a lesser extent - from MEK/MAPK and mTOR inhibition. Inhibition of JAK/STAT or PLCgamma did not affect cell proliferation. Similarly, only PI3-K inhibition resulted in substantial apoptosis in the imatinib-resistant GISTs. We conclude that GIST secondary KIT mutations can be associated with KIT hyperactivation and imatinib resistance. Targeting critical downstream signaling proteins, such as PI3-K, is a promising therapeutic strategy in imatinib-resistant GISTs.
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PMID:KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. 1754 49

Stress dramatically affects the induction of hippocampal synaptic plasticity; however, the molecular details of how it does so remain unclear. Phosphatidylinositol 3-kinase (PI3K) signaling plays a crucial role in promoting neuronal survival and neuroplasticity, but its role, if any, in stress-induced alterations of long term potentiation (LTP) and long term depression (LTD) is unknown. We found here that inhibitors of PI3K signaling blocked the effects of acute restraint-tail shock stress protocol on LTP and LTD. Therefore, the purpose of the present study is to explore the signaling events involving PI3K in terms of its role in mediating stress protocol-induced alterations of LTP and LTD. We found that stress protocol-induced PI3K activation can be blocked by various inhibitors, including RU38486 for glucocorticoid receptors, LY294002 for PI3K, and dl-2-amino-5-phosphonopentanoic acid for N-methyl-D-aspartate receptors or brain-derived neurotrophic factor antisense oligonucleotides. Also, immunoblotting analyses revealed that stress protocol induced a profound and prolonged phosphorylation of numbers of PI3K downstream effectors, including 3-phosphoinositide-dependent protein kinase-1, protein kinase B, mammalian target of rapamycin (mTOR), p70 S6 kinase, and eukaryotic initiation factor 4B in hippocampal CA1 homogenate, which was prevented by the PI3K inhibitor pretreatment. More importantly, we found that stress protocol significantly increased the protein expression of dendritic scaffolding protein PSD-95 (postsynaptic density-95), which is known to be involved in LTP and LTD, in an mTOR-dependent manner. These results identify a key role of PI3K signaling in mediating the stress protocol-induced modification of hippocampal synaptic plasticity and further suggest that PI3K may do so by invoking the protein expression of PSD-95.
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PMID:Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity. 1805 5


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