Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002
| Autor: | Brunn, G J, Williams, J, Sabers, C, Wiederrecht, G, Lawrence, J C, Abraham, R T |
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| Jazyk: | angličtina |
| Rok vydání: | 1996 |
| Předmět: |
Morpholines
Recombinant Fusion Proteins T-Lymphocytes Cell Cycle Proteins Polyenes Lymphocyte Activation Lymphoma T-Cell Cell Line Mice Phosphatidylinositol 3-Kinases Adenosine Triphosphate Tumor Cells Cultured Animals Enzyme Inhibitors Eukaryotic Initiation Factors Phosphorylation Adaptor Proteins Signal Transducing Brain Chemistry Sirolimus TOR Serine-Threonine Kinases Intracellular Signaling Peptides and Proteins Phosphoproteins Rats Androstadienes Dithiothreitol Phosphotransferases (Alcohol Group Acceptor) Chromones Interleukin-2 Carrier Proteins Wortmannin Protein Kinases Immunosuppressive Agents Research Article Signal Transduction T-Lymphocytes Cytotoxic |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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