Abstract
Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis*
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases*
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Cysteine Endopeptidases / metabolism*
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Cytochrome c Group / metabolism
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Enzyme Activation
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Etoposide / pharmacology
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Gene Expression Regulation
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Humans
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Inhibitor of Apoptosis Proteins
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Mitochondria / metabolism
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NF-kappa B / metabolism*
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Proteins / genetics*
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Proteins / physiology
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Signal Transduction
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitin-Protein Ligases
Substances
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Cytochrome c Group
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Inhibitor of Apoptosis Proteins
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NF-kappa B
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Proteins
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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Etoposide
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases
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Cysteine Endopeptidases