Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor family that selectively induces apoptosis of cancer cells. However, some cancer cells or subpopulations within cancer cell lines are resistant to TRAIL-induced apoptosis. We developed a retroviral cDNA library-based functional cloning approach to unambiguously identify putative inhibitory genes of TRAIL-induced apoptosis. This effort identified the short splice form of Casper/c-FLIP, Casper-S/c-FLIPs, as a major cellular protein that confers resistance to TRAIL-induced apoptosis. Furthermore, we found that Casper deficient embryonic fibroblasts (EFs) were highly sensitive while their wild-type counterparts were completely resistant to TRAIL-induced apoptosis. Retroviral-mediated transduction of Casper-S/c-FLIPs into Casper(-/-) EFs restored resistance to TRAIL. These data suggest that Casper-S/c-FLIPs is a major cellular inhibitor of TRAIL-induced apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis Regulatory Proteins
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Apoptosis*
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / metabolism
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins*
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Ligands
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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Protein Synthesis Inhibitors / pharmacology
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RNA Splicing*
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Serpins / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Viral Proteins*
Substances
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Cysteine Proteinase Inhibitors
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins
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Protein Synthesis Inhibitors
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Serpins
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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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Viral Proteins
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interleukin-1beta-converting enzyme inhibitor
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Cycloheximide