title: NF-kappa B activation results in rapid inactivation of JNK in TNF alpha-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-kappa B.
abstract: We recently reported that inhibition of NF-kappa B activation as a consequence of the overexpression of a degradation-resistant form of I kappa B alpha [I kappa B alpha(A32/36)] sensitized Ewing sarcoma cells to TNF alpha-induced killing. The c-Jun N-terminal kinases (JNK) have been shown to participate in death signaling triggered by certain stimuli and are activated by TNF alpha. To obtain insight into the mechanism of the anti-apoptotic effect of NF-kappa B, we compared the profiles of JNK activation by TNF alpha in control cells and in cells in which NF-kappa B activation was impaired. We show here that JNK activation was transient in control cells but remained elevated in I kappa B alpha(A32/36)-expressing cells. NF-kappa B repressed specifically the JNK pathway, since the kinetics of activation of the other TNF alpha-activated-MAP kinase p38 were identical in both cells. Prolongation of JNK activation in I kappa B alpha(A32/36)-expressing cells was not inhibited by the broad spectrum caspase inhibitor Z-VAD-FMK and thus was not the consequence of caspase activation. Pretreatment of control cells with the phosphatase inhibitor vanadate greatly prolonged JNK activation by TNF alpha and resulted in induction of apoptosis by this cytokine. Moreover, overexpression of a dominant-negative mutant of JNK1 decreased TNF alpha-induced apoptosis in cells expressing the super repressor of NF-kappa B, indicating that the sustained activation of JNK1 participated in death signaling triggered by TNF alpha. Our results provide evidence that the repression of JNK activation by NF-kappa B participates in the anti-apoptotic effect of this transcription factor in TNF alpha-treated Ewing sarcoma cells.
authors.affiliation: INSERM U365, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: D
authors.initials: D
authors.lastname: Javelaud
authors.forename: F
authors.initials: F
authors.lastname: Besançon
mesh_terms: D017209:Apoptosis; D001859:Bone Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020169:Caspases / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005656:Fungal Proteins; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases