c-Jun NH2-terminal kinase activation leads to a FADD-dependent but Fas ligand-independent cell death in Jurkat T cells.
Persistent c-Jun NH2-terminal kinase (JNK) activation induces cell death. Different mechanisms are ascribed to JNK-induced cell death. Most of the JNK-apoptosis studies employ stress stimuli known to activate kinases other than JNK. Here we used overexpression of mitogen-activated protein kinase kinase 7 (MKK7) to activate selectively JNK in T lymphoma Jurkat cells. Similar to that reported previously, Fas ligand (FasL) expression was up-regulated by JNK activation. Dominant negative-FADD and caspase-8 inhibitor benzyloxycarbonyl-Ile-Glu-Thr-Asp effectively inhibited MKK7-induced cell death, supporting a major involvement of FADD cascade. However, MKK7-induced cell death was not prevented by antagonist antibody ZB4 and Fas-Fc, indicating that Fas-FasL interaction is minimally involved. Confocal microscopy revealed that persistent JNK activation led to clustering of Fas. Our results suggest that, in contrast to that reported previously, JNK alone-induced death in Jurkat cells is FADD-dependent but is not triggered by Fas-FasL interaction.
Chen
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Institute of Molecular Biology, Academia Sinica, and the Graduate Institute of Immunology, National Taiwan University School of Medicine, Taipei 11529, Taiwan.
Lai
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MZ
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D048688:MAP Kinase Kinase 7; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9