title: Apoptosis induced by a chimeric Fas/FLICE receptor: lack of requirement for Fas- or FADD-binding proteins.
abstract: Current models for Fas (CD95)-mediated apoptosis suggest that FLICE/caspase-8 is recruited and activated, which results in cell death. However, the role of additional molecules in Fas signaling and FLICE activation is not clear. A chimeric Fas/FLICE (F/F) receptor, containing the extracellular/transmembrane portion of Fas and the caspase region of FLICE, mediated anti-Fas apoptosis. FLICE protease subunits were generated from the F/F precursor. Killing induced by Fas, but not F/F, was blocked by a dominant negative FADD. Apoptosis triggered through Fas and F/F was inhibited by coexpression of CrmA and p35, but not Bcl-xL. F/F bypassed Fas resistance in COS-7 cells and blocking by the death effector domain (DED)-containing viral protein MC159. These results show that: 1) F/F induces cell death, indicating that FLICE activation is sufficient for apoptosis and does not require additional Fas- or FADD-binding proteins; and 2) F/F bypasses proximal defects in Fas signaling that prevent FLICE recruitment or activation.
authors.affiliation: Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Memon
authors.forename: J
authors.initials: J
authors.lastname: Hou
authors.forename: M B
authors.initials: MB
authors.lastname: Moreno
authors.forename: C M
authors.initials: CM
authors.lastname: Zacharchuk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005799:Genes, Dominant / Q000276:immunology; D006825:Hybridomas; D051034:Inhibitor of Apoptosis Proteins; D007939:Leukemia L1210; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000276:immunology* / Q000502:physiology; D015843:Serpins / Q000502:physiology; D013601:T-Lymphocytes; D014764:Viral Proteins / Q000502:physiology; D051020:bcl-X Protein; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D015843:Serpins; D014764:Viral Proteins; D051020:bcl-X Protein; D019014:fas Receptor; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; C074641:interleukin-1beta-converting enzyme inhibitor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases