title: Modulation of the sensitivity of Jurkat T-cells to inhibition of protein synthesis by tumor necrosis factor α-related apoptosis-inducing ligand.
abstract: Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in Jurkat T lymphoma cells. One of the characteristics of the phase preceding overt apoptosis is the marked downregulation of protein synthesis. We have investigated factors that can influence this response and have explored some of the signaling pathways involved. We show that interferon-α (IFNα) pretreatment desensitizes Jurkat cells to TRAIL-induced inhibition of protein synthesis, such that the concentration of TRAIL required for 50% inhibition is increased by 10-fold. The inhibition of translation is characterized by dephosphorylation of the eIF4E-binding protein 4E-BP1 and IFNα desensitizes Jurkat cells to this effect. IFNα also inhibits TRAIL-mediated dephosphorylation of the growth-promoting protein kinase B (Akt). Since Jurkat cells are defective for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and therefore have constitutive phosphoinositide 3-kinase (PI3K) activity, we investigated the consequences for protein synthesis of inhibiting PI3K using LY294002. Inhibition of PI3K partially inhibits translation, but also enhances the effect of a suboptimal concentration of TRAIL. However, LY294002 does not block the ability of IFNα to protect protein synthesis from TRAIL-induced inhibition. Data are presented suggesting that IFNα impairs the process of activation of caspase-8 within the TRAIL death-inducing signaling complex.
authors.affiliation: 1 Translational Control Group, Molecular Cell Sciences Research Centre, St George's, University of London , London, United Kingdom .
authors.forename: Androulla
authors.initials: A
authors.lastname: Elia
authors.forename: Ian R
authors.initials: IR
authors.lastname: Powley
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D056747:Immunomodulation; D016898:Interferon-alpha / Q000276:immunology; D019169:Jurkat Cells; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053181:Caspase 8; D018797:Cell Cycle Proteins; D002867:Chromones; D016898:Interferon-alpha; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C087000:EIF4EBP1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one