title: 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.
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.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Siegmund
authors.forename: D
authors.initials: D
authors.lastname: Mauri
authors.forename: N
authors.initials: N
authors.lastname: Peters
authors.forename: P
authors.initials: P
authors.lastname: Juo
authors.forename: M
authors.initials: M
authors.lastname: Thome
authors.forename: M
authors.initials: M
authors.lastname: Reichwein
authors.forename: J
authors.initials: J
authors.lastname: Blenis
authors.forename: P
authors.initials: P
authors.lastname: Scheurich
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
authors.forename: H
authors.initials: H
authors.lastname: Wajant
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005786:Gene Expression Regulation; D016762:Genes, fos; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000502:physiology*; D008954:Models, Biological; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases