Abstract
We recently reported that inhibition of NF-κB activation as a consequence of the overexpression of a degradation-resistant form of IκBα [IκBα(A32/36)] sensitized Ewing sarcoma cells to TNFα-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 TNFα. To obtain insight into the mechanism of the anti-apoptotic effect of NF-κB, we compared the profiles of JNK activation by TNFα in control cells and in cells in which NF-κB activation was impaired. We show here that JNK activation was transient in control cells but remained elevated in IκBα(A32/36)-expressing cells. NF-κB repressed specifically the JNK pathway, since the kinetics of activation of the other TNFα-activated-MAP kinase p38 were identical in both cells. Prolongation of JNK activation in IκBα(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 TNFα and resulted in induction of apoptosis by this cytokine. Moreover, overexpression of a dominant-negative mutant of JNK1 decreased TNFα-induced apoptosis in cells expressing the super repressor of NF-κB, indicating that the sustained activation of JNK1 participated in death signaling triggered by TNFα. Our results provide evidence that the repression of JNK activation by NF-κB participates in the anti-apoptotic effect of this transcription factor in TNFα-treated Ewing sarcoma cells.
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Acknowledgements
We thank Dr O Delattre and Pr G Lenoir for providing the EW7 cells and Dr A Atfi for the mutant JNK1 plasmid. We also thank Drs MF Bourgeade, G Cherqui and A Atfi for helpful discussions. We are grateful to C Silvestri for skilful technical help and to Pr H Ankel for editing assistance. This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants of the Comité de Paris de la Ligue Nationale contre le Cancer and the Association pour la Recherche sur le Cancer (ARC). D Javelaud is a recipient of a fellowship from ARC.
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Javelaud, D., Besançon, F. NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-κB. Oncogene 20, 4365–4372 (2001). https://doi.org/10.1038/sj.onc.1204570
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DOI: https://doi.org/10.1038/sj.onc.1204570
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