Abstract
We have recently shown that stimulation of TNF-R2 selectively enhances apoptosis induction by the death receptor TNF-R1. Here, we demonstrate that stimulation of CD30 or CD40 also leads to selective enhancement of TNF-R1-induced cell death. Enhancement of apoptosis was correlated with the depletion of endogenous TRAF2 within 1 to 6 hours. Selective prestimulation of TNF-R2 for several hours inhibited TNF-R2-induced activation of the anti-apoptotic NF-kappaB pathway up to 90% and dramatically enhanced apoptosis induction by this receptor. When both TNF-receptors were stimulated simultaneously, TNF-R1-induced NF-kappaB activation remained unaffected but TNF-R1-induced apoptosis was still significantly enhanced. Compared with FasL-induced cell death TNF-R1-induced activation of caspase-8 was significantly weaker and delayed. Costimulation or prestimulation of TNF-R2 enhanced caspase-8 processing. Life cell imaging and confocal microscopy revealed that both TNF-R1 and TNF-R2 recruited the anti-apoptotic factor cIAP1 in a TRAF2-dependent manner. Thus, TNF-R2 may compete with TNF-R1 for the recruitment of newly synthesized TRAF2-bound anti-apoptotic factors, thereby promoting the formation of a caspase-8-activating TNF-R1 complex. Hence, TNF-R2 triggering can interfere with TNF-R1-induced apoptosis by inhibition of NF-kappaB-dependent production of anti-apoptotic factors and by blocking the action of anti-apoptotic factors at the post-transcriptional level.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Protein Complex 2 / genetics
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Apoptosis / drug effects
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Apoptosis / genetics*
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Apoptosis Regulatory Proteins
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CD40 Antigens / genetics
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CD40 Antigens / metabolism
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Caspase 8
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Caspase 9
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Caspases / genetics
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Caspases / metabolism*
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Down-Regulation / genetics*
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Eukaryotic Cells / drug effects
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Eukaryotic Cells / metabolism*
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Fas Ligand Protein
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HeLa Cells
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Humans
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Inhibitor of Apoptosis Proteins
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Insect Proteins / genetics
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Insect Proteins / metabolism*
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Ki-1 Antigen / genetics
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Ki-1 Antigen / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Models, Biological
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Proteins / genetics
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Proteins / metabolism
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Rhabdomyosarcoma
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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TNF-Related Apoptosis-Inducing Ligand
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Transcription Factor AP-1 / genetics
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Ubiquitin-Protein Ligases
Substances
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Adaptor Protein Complex 2
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Antigens, CD
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Apoptosis Regulatory Proteins
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CD40 Antigens
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FASLG protein, human
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Fas Ligand Protein
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Inhibitor of Apoptosis Proteins
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Insect Proteins
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Ki-1 Antigen
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Membrane Glycoproteins
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Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases