Abstract
Fas, a death domain-containing member of the tumor necrosis factor receptor family and its ligand FasL have been predominantly studied with respect to their capability to induce cell death. However, a few studies indicate a proliferation-inducing signaling activity of these molecules too. We describe here a novel signaling pathway of FasL and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that triggers transcriptional activation of the proto-oncogene c-fos, a typical target gene of mitogenic pathways. FasL- and TRAIL-mediated up-regulation of c-Fos was completely dependent on the presence of Fas-associated death domain protein (FADD) and caspase-8, but caspase activity seemed to be dispensable as a pan inhibitor of caspases had no inhibitory effect. Upon overexpression of the long splice form of cellular FADD-like interleukin-1-converting enzyme (FLICE) inhibitory protein (cFLIP) in Jurkat cells, FasL- and TRAIL-induced up-regulation of c-Fos was almost completely blocked. The short splice form of FLIP, however, showed a rather stimulatory effect on c-Fos induction. Together these data demonstrate the existence of a death receptor-induced, FADD- and caspase-8-dependent pathway leading to c-Fos induction that is inhibited by the long splice form FLIP-L.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Alternative Splicing
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Antibodies, Monoclonal / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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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 / metabolism*
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Fas Ligand Protein
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Fas-Associated Death Domain Protein
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Gene Expression Regulation*
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Genes, fos*
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Humans
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Intracellular Signaling Peptides and Proteins*
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Jurkat Cells
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Membrane Glycoproteins / physiology*
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Models, Biological
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-fos / genetics
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Recombinant Proteins / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Transfection
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Tumor Necrosis Factor-alpha / physiology*
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fas Receptor / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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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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FADD protein, human
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FASLG protein, human
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Fas Ligand Protein
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Fas-Associated Death Domain Protein
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Intracellular Signaling Peptides and Proteins
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MAS1 protein, human
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Membrane Glycoproteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-fos
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Recombinant Proteins
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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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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