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Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway.
Journal of Biological Chemistry
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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.
Adaptor Proteins, Signal Transducing, Alternative Splicing, Antibodies, Monoclonal/pharmacology, Antigens, CD95/physiology, Apoptosis/drug effects, Apoptosis/physiology, Apoptosis Regulatory Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins/genetics, Carrier Proteins/metabolism, Caspase 8, Caspase 9, Caspases/metabolism, Fas Ligand Protein, Fas-Associated Death Domain Protein, Gene Expression Regulation, Genes, fos, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Membrane Glycoproteins/physiology, Models, Biological, Proto-Oncogene Proteins c-fos/genetics, Recombinant Proteins/metabolism, TNF-Related Apoptosis-Inducing Ligand, Transfection, Tumor Necrosis Factor-alpha/physiology
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