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JNK/SAPK activity contributes to TRAIL-induced apoptosis
1Division of Molecular Oncology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Abstract:
We report here that JNK/SAPKs are activated by TRAIL in parallel to induction of apoptosis in human T and B cell lines. Death signaling as well as JNK/SAPK activation by TRAIL in these cells is FADD- and caspase-dependent since dominant-negative FADD or the caspase inhibitor zVAD prevented both, apoptosis and JNK/SAPK activity. JNK/SAPK activity in response to triggering of CD95 by an agonistic antibody (alphaAPO-1) was also diminished by dominant-negative FADD or zVAD. Correspondingly, a cell line resistant to alphaAPO-1-induced death exhibited crossresistance to TRAIL-induced apoptosis and did not upregulate JNK/SAPK activity in response to TRAIL or alphaAPO-1. Inhibition of JNK/SAPK activity, by stably transfecting cells with a dominant-negative JNKK-MKK4 construct, reduced apoptosis in response to TRAIL or alphaAPO-1. Therefore, activation of JNK/SAPKs by TRAIL or alphaAPO-1 occurs downstream of FADD and caspases and contributes to apoptosis in human lymphoid cell lines.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates JNK/SAPK pathways, promoting apoptosis in human T and B cells. This signaling is dependent on FADD and caspases, with JNK/SAPK activation contributing to cell death.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- TRAIL and CD95 receptor pathways are critical in initiating apoptosis in lymphoid cells.
- JNK/SAPK signaling is implicated in cellular stress responses and programmed cell death.
Purpose of the Study:
- To investigate the role of JNK/SAPK activation in TRAIL- and CD95-mediated apoptosis in human T and B cell lines.
- To elucidate the relationship between death receptor signaling, FADD, caspases, and JNK/SAPK activation.
Main Methods:
- Utilized dominant-negative FADD and caspase inhibitor zVAD to block apoptosis and JNK/SAPK activation.
- Employed an agonistic antibody (alphaAPO-1) to trigger CD95 signaling.
- Generated a cell line resistant to CD95-induced apoptosis for cross-resistance studies.
- Inhibited JNK/SAPK activity using a dominant-negative JNKK-MKK4 construct.
Main Results:
- TRAIL induced JNK/SAPK activation in parallel with apoptosis in human T and B cell lines.
- FADD and caspase inhibition abrogated both TRAIL-induced apoptosis and JNK/SAPK activation.
- CD95 triggering also led to FADD- and caspase-dependent JNK/SAPK activation.
- A CD95-resistant cell line showed cross-resistance to TRAIL and lacked TRAIL/CD95-induced JNK/SAPK upregulation.
- Inhibition of JNK/SAPK signaling attenuated TRAIL- and CD95-induced apoptosis.
Conclusions:
- JNK/SAPK activation by TRAIL and CD95 occurs downstream of FADD and caspases.
- JNK/SAPK pathway activation contributes to TRAIL- and CD95-mediated apoptosis in human lymphoid cells.