Abstract
We report here that stress stimuli such as gamma-irradiation or the anticancer drug doxorubicin activate expression of the death-inducing ligands (DILs) CD95-L, TNF-alpha and TRAIL. Apoptosis induced by gamma-irradiation or doxorubicin engages a FADD- and caspase-dependent apoptosis pathway which is inhibited by dominant negative FADD or the caspase inhibitor zVAD. zVAD did not prevent activity of JNK/SAPKs in response to doxorubicin suggesting that JNK/SAPK activity is independent of death receptor triggering during cellular stress-induced apoptosis. In addition, JNK/SAPKs remained activated by doxorubicin in resistant cell lines in which cleavage of caspases and apoptosis was not observed. These data uncouple JNK/SAPK activation and apoptosis signaling and indicate that cellular stress-induced apoptosis involves signaling via DILs which is paralleled by activation of JNK/SAPKs. Activation of these kinases may contribute e.g., to the expression of molecules involved in apoptosis but is not sufficient for induction of the apoptosis program following cellular stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Arabidopsis Proteins*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Caspases / metabolism
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Doxorubicin / pharmacology
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Enzyme Activation
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Fatty Acid Desaturases / metabolism
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Humans
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Jurkat Cells / drug effects
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Jurkat Cells / radiation effects
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Membrane Glycoproteins / metabolism*
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Mitogen-Activated Protein Kinases*
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Neoplasm Proteins / metabolism*
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Plant Proteins / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / radiation effects
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Tumor Necrosis Factor-alpha / metabolism*
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Up-Regulation
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fas Receptor / metabolism*
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p38 Mitogen-Activated Protein Kinases
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Arabidopsis Proteins
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Membrane Glycoproteins
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Neoplasm Proteins
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Plant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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fas Receptor
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Doxorubicin
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Fatty Acid Desaturases
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Fad7 protein, Arabidopsis
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Caspases