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• W2004233777 abstract "Death ligands not only activate a death program but also regulate inflammatory signalling pathways, for example, through NF-κB induction. Although tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF both activate NF-κB in human keratinocytes, only TRAIL potently induces apoptosis. However, when induction of NF-κB was inhibited with a kinase dead IKK2 mutant (IKK2-KD), TNF- but not TRAIL-induced apoptosis was dramatically enhanced. Acquired susceptibility to TNF-induced apoptosis was due to increased caspase-8 activation. To investigate the mechanism of resistance of HaCaT keratinocytes to TNF-induced apoptosis, we analyzed a panel of NF-κB-regulated effector molecules. Interestingly, the inhibitor of apoptosis protein (IAP) family member cIAP2, but not cIAP1, X-linked inhibitor of apoptosis, TNF receptor-associated factor (TRAF)-1, or TRAF2, was downregulated in sensitive but not in resistant HaCaT keratinocytes. Surprisingly, however, stable inducible expression of cIAP2 was not sufficient to render IKK2-KD-sensitized keratinocytes resistant to TNF, and reduction of cIAP2 alone did not increase the sensitivity of HaCaT keratinocytes to TNF. In conclusion, we demonstrate that inhibition of NF-κB dramatically sensitizes human keratinocytes to TNF- but not to TRAIL-induced apoptosis and that this sensitization for TNF was largely independent of cIAP2. Our data thus clearly exclude the candidates proposed to date to confer TNF apoptosis resistance and suggest the function of an unanticipated effector of NF-κB critical for the survival of HaCaT keratinocytes upstream or at the level of caspase-8 activation. Death ligands not only activate a death program but also regulate inflammatory signalling pathways, for example, through NF-κB induction. Although tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF both activate NF-κB in human keratinocytes, only TRAIL potently induces apoptosis. However, when induction of NF-κB was inhibited with a kinase dead IKK2 mutant (IKK2-KD), TNF- but not TRAIL-induced apoptosis was dramatically enhanced. Acquired susceptibility to TNF-induced apoptosis was due to increased caspase-8 activation. To investigate the mechanism of resistance of HaCaT keratinocytes to TNF-induced apoptosis, we analyzed a panel of NF-κB-regulated effector molecules. Interestingly, the inhibitor of apoptosis protein (IAP) family member cIAP2, but not cIAP1, X-linked inhibitor of apoptosis, TNF receptor-associated factor (TRAF)-1, or TRAF2, was downregulated in sensitive but not in resistant HaCaT keratinocytes. Surprisingly, however, stable inducible expression of cIAP2 was not sufficient to render IKK2-KD-sensitized keratinocytes resistant to TNF, and reduction of cIAP2 alone did not increase the sensitivity of HaCaT keratinocytes to TNF. In conclusion, we demonstrate that inhibition of NF-κB dramatically sensitizes human keratinocytes to TNF- but not to TRAIL-induced apoptosis and that this sensitization for TNF was largely independent of cIAP2. Our data thus clearly exclude the candidates proposed to date to confer TNF apoptosis resistance and suggest the function of an unanticipated effector of NF-κB critical for the survival of HaCaT keratinocytes upstream or at the level of caspase-8 activation. antibody c-FLICE inhibitory protein long form constitutively active Fas-associated death domain protein 4-hydroxytamoxifen inhibitor of apoptosis protein kinase dead small interfering RNA tumor necrosis factor TNF receptor-associated factor TNF-related apoptosis-inducing ligand X-linked inhibitor of apoptosis" @default.
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• W2004233777 date "2008-05-01" @default.
• W2004233777 modified "2023-10-16" @default.
• W2004233777 title "NF-κB Inhibition Reveals Differential Mechanisms of TNF Versus TRAIL-Induced Apoptosis Upstream or at the Level of Caspase-8 Activation Independent of cIAP2" @default.
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• W2004233777 doi "https://doi.org/10.1038/sj.jid.5701141" @default.
• W2004233777 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17989734" @default.
• W2004233777 hasPublicationYear "2008" @default.
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