Abstract
c-FLIP proteins (isoforms: c-FLIP(L), c-FLIP(S), and c-FLIP(R)) play an essential role in the regulation of death receptor-induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor kappaB (NF-kappaB) activity by interacting with the IkappaB kinase (IKK) complex via the IKKgamma subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappaB activation and life/death decisions in lymphocytes and DCs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Caspase 8
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Caspases / metabolism
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Cytoplasm / metabolism
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Cytoplasm / pathology
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Humans
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I-kappa B Kinase / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism*
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Jurkat Cells
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Mice
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NF-kappa B / metabolism*
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Neoplasm Proteins / metabolism*
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Neoplasms / metabolism
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Neoplasms / pathology
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Protein Binding
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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Signal Transduction*
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Cflar protein, mouse
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Neoplasm Proteins
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Protein Isoforms
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I-kappa B Kinase
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases