Abstract
CD95 (Fas/APO-1) and tumor necrosis factor receptor-1 (TNFR-1) are related molecules that signal apoptosis. Recently, a number of novel binding proteins have been proposed to mediate the signaling of these death receptors. Here we report that an N-terminal truncation of one of these candidate signal transducers, FADD/MORT1, abrogates CD95-induced apoptosis, ceramide generation, and activation of the cell death protease Yama/CPP32. In addition, this dominant-negative derivative of FADD (FADD-DN) blocked TNF-induced apoptosis while not affecting NF- kappaB activation. FADD-DN bound both receptors, and in the case of CD95, it disrupted the assembly of a signaling complex. Taken together, our results functionally establish FADD as the apoptotic trigger of CD95 and TNFR-1.
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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Animals
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Antibodies
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Apoptosis*
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Breast Neoplasms
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Carrier Proteins / physiology*
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Cell Death
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Cell Line
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Cell Survival
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Ceramides / metabolism
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Fas-Associated Death Domain Protein
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Female
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Humans
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Immunoglobulin M / pharmacology
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Kinetics
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Lymphoma, B-Cell
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Rabbits / immunology
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Receptors, Tumor Necrosis Factor / physiology*
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Recombinant Proteins / metabolism
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Signal Transduction
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Transfection
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Tumor Cells, Cultured
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fas Receptor / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies
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Carrier Proteins
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Ceramides
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FADD protein, human
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Fas-Associated Death Domain Protein
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Immunoglobulin M
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Peptide Fragments
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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fas Receptor