Abstract
Fas is a surface receptor that can transmit signals for apoptosis. Using retroviral cDNA library-based functional cloning we identified a gene, toso, that blocks Fas-mediated apoptosis. Toso expression was confined to lymphoid cells and was enhanced after cell-specific activation processes in T cells. Toso appeared limited to inhibition of apoptosis mediated by members of the TNF receptor family and was capable of inhibiting T cell self-killing induced by TCR activation processes that up-regulate Fas ligand. We mapped the effect of Toso to inhibition of caspase-8 processing, the most upstream caspase activity in Fas-mediated signaling, potentially through activation of cFLIP. Toso therefore serves as a novel regulator of Fas-mediated apoptosis and may act as a regulator of cell fate in T cells and other hematopoietic lineages.
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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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Base Sequence
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 8
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Caspase 9
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Caspases*
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Cloning, Molecular
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Cysteine Endopeptidases / metabolism
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DNA Primers / genetics
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Fas-Associated Death Domain Protein
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Humans
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Intracellular Signaling Peptides and Proteins*
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Lymphocyte Activation
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Molecular Sequence Data
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Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Signal Transduction
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T-Lymphocytes / cytology*
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T-Lymphocytes / immunology
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T-Lymphocytes / physiology*
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Tumor Necrosis Factor-alpha / metabolism
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fas Receptor / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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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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DNA Primers
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FADD protein, human
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FCMR protein, human
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Fas-Associated Death Domain Protein
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Tumor Necrosis Factor-alpha
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fas Receptor
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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
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Cysteine Endopeptidases