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Dominant-Negative Fas Mutation Is Reversed by Down-expression of c-FLIP

Laboratoire Composantes Innées de la Réponse Immunitaire et Différenciation, Centre National de la Recherche Scientifique UMR 5164, University of Bordeaux 2, Bordeaux, France

Requests for reprints: Patrick Legembre or Jean-Luc Taupin, Laboratoire Composantes Innées de la Réponse Immunitaire et Différenciation, Centre National de la Recherche Scientifique UMR 5164, University of Bordeaux 2, 146 rue Léo Saignat, Bordeaux 33076, France. Phone: 33-55757-1471; Fax: 33-55757-1472; E-mail: plege{at}u-bordeaux2.fr or jean-luc.taupin{at}u-bordeaux2.fr.

Fas triggering by agonistic antibodies or by its cognate ligand, FasL, induces apoptotic cell death, whereas mutation in the Fas death domain is associated with lymphoma progression. On prolonged culture in the presence of an agonistic anti-Fas antibody, we raised a Jurkat cell line resistant to agonistic antibodies but still sensitive to soluble FasL, which carried at the heterozygous state, a point mutation into the Fas death domain. Down-modulation of c-FLIP expression reversed the blockade of the Fas pathway. We show that the activation threshold for the Fas receptor is more easily overcome by multimeric FasL than by agonistic antibodies and that the increase of this threshold due to mutation in the Fas death domain can be overcome by acting on a downstream effector of the Fas signal, c-FLIP. These findings put forward a new approach to eradicate Fas-resistant tumor cells. [Cancer Res 2007;67(1):108–15]

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