TNF-induced mitochondrial changes and activation of apoptotic proteases are inhibited by A20.
A20 zinc finger protein is a product of a cytokine-induced primary response gene. It functions as a negative regulator of the tumor necrosis factor (TNF) inhibiting both TNF-mediated apoptosis and activation of transcription factors. We demonstrated that A20 overexpression blocks early TNF-induced signaling events including the generation of free radicals, the fall in mitochondrial transmembrane potential (delta psi(m)), and the activation of caspase-3-like apoptotic proteases. General inhibitor of caspases, cow pox virus-derived CrmA, also inhibited TNF-induced mitochondrial changes indicating that early caspase activation occurs upstream from mitochondrial changes. Interestingly, changes in mitochondrial function or induction of caspase-3-like activity induced by anti-Fas or doxorubicin were not inhibited by A20. The data show that A20 is a specific inhibitor of TNF signaling and acts upstream of INF-induced free radical formation, fall in mitochondrial transmembrane potential (delta psi(m)), and activation of caspase-3-like proteases.
Wissing
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Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Copenhagen.
Mouritzen
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Jäättelä
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D009687:Nuclear Proteins; D011480:Protease Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016335:Zinc Fingers / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011480:Protease Inhibitors; D011506:Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004317:Doxorubicin; D010450:Endopeptidases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse