title: Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.
abstract: Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.
authors: Unité Mixte de Recherche Centre National de la Recherche Scientifique 5164, Université de Bordeaux 2, Bordeaux, France.
authors: Sophie
authors: S
authors: Daburon
authors: Christel
authors: C
authors: Devaud
authors: Pierre
authors: P
authors: Costet
authors: Aurore
authors: A
authors: Morello
authors: Laure
authors: L
authors: Garrigue-Antar
authors: Mike
authors: M
authors: Maillasson
authors: Nathalie
authors: N
authors: Hargous
authors: Delphine
authors: D
authors: Lapaillerie
authors: Marc
authors: M
authors: Bonneu
authors: Julie
authors: J
authors: Dechanet-Merville
authors: Patrick
authors: P
authors: Legembre
authors: Myriam
authors: M
authors: Capone
authors: Jean-François
authors: JF
authors: Moreau
authors: Jean-Luc
authors: JL
authors: Taupin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000235:genetics*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D015514:Oncogene Proteins, Fusion; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins; D019014:fas Receptor