TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase- dependent and caspase-independent pathways

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Abstract

In this study we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also called Apo2L, activates the c-Jun N-terminal kinase (JNK). Interestingly, TRAIL-induced JNK activation occurs in a cell type-specific manner. In HeLa cells, TRAIL-induced JNK activation can be completely blocked with the cysteine protease inhibitor zVAD-fmk, whereas the same inhibitor has no, or even a stimulatory, effect on JNK activation in Kym-1 cells. Hence, TRAIL can engage at least two independent pathways leading to JNK activation, one that is cysteine protease-dependent and one that is cysteine protease-independent. To investigate whether the cysteine protease-dependent signaling of TRAIL leading to JNK activation is related to the apoptotic pathway engaged by this ligand, we investigated HeLa cells stably overexpressing a dominant negative mutant of FADD (Fas-associating protein with death domain) (GFP(green fluorescent protein)ΔFADD). In these cells, TRAIL-induced cell death and activation of the apoptosis executioner caspase-8 (FLICE/MACH) and caspase-3 (YAMA, CPP-32, Apopain), that belong to caspase subfamily of cysteine proteases, were abrogated, whereas JNK activation remained unaffected and was still sensitive toward z-VAD-fmk. Similar data were found in HeLa cells overexpressing Apo1/Fas and GFPΔFADD upon stimulation with agonistic antibodies. These data suggest that cross- linking of the TRAIL receptors and Apo1/Fas, respectively, engages a FADD- dependent pathway leading to the activation of apoptotic caspases and, in parallel, a FADD-independent pathway leading to the stimulation of one or more cysteine proteases capable to activate JNK but not sufficient for the induction of cell death.

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Mühlenbeck, F., Haas, E., Schwenzer, R., Schubert, G., Grell, M., Smith, C., … Wajant, H. (1998). TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase- dependent and caspase-independent pathways. Journal of Biological Chemistry, 273(49), 33091–33098. https://doi.org/10.1074/jbc.273.49.33091

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