title: A novel signaling mechanism for soluble CD95 ligand. Synergy with anti-CD95 monoclonal antibodies for apoptosis and NF-kappaB nuclear translocation.
abstract: Soluble CD95 (Fas) ligand (sFasL) is known to be deficient in transducing signals upon engagement with membrane Fas. Here we report that sFasL tranduces, in synergy with non-cytotoxic anti-Fas monoclonal antibody (mAb), signals for apoptosis and nuclear translocation of the NF-kappaB (p65/p50) heterodimer. Activation of the specific signaling pathways correlates with target Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein expression. Synergy with anti-Fas mAb was demonstrated with a trimeric unit of sFasL bearing a single binding site for Fas trimer. In contrast, membrane-bound FasL as expressed on cell-derived vesicles was fully competent in transducing Fas-mediated signals for apoptosis and NF-kappaB nuclear translocation. We propose a model in which the trimeric sFasL signaling requires target expression of a high focal density of Fas, which is induced by the signaling-incompetent anti-Fas mAb. Membrane-bound FasL induces powerful Fas-mediated signals because it possesses both Fas-focusing and signal-transducing functions.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Satoshi
authors.initials: S
authors.lastname: Jodo
authors.forename: Sun-Sang J
authors.initials: SS
authors.lastname: Sung
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Shyr-Te
authors.initials: ST
authors.lastname: Ju
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D001483:Base Sequence; D017931:DNA Primers; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015345:Oligonucleotide Probes; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D019014:fas Receptor