Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL

Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x_L

^*The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Vic 3050, Melbourne, Australia; ^†Institute for Biochemistry, University of Lausanne, Chemin de Boveresses 155, CH-1066, Epalinges, Switzerland; and ^§Department of Neurosurgery and ^¶Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland

Communicated by Suzanne Cory, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia (received for review September 21, 1999)

Abstract

Fas activation triggers apoptosis in many cell types. Studies with anti-Fas antibodies have produced conflicting results on Fas signaling, particularly the role of the Bcl-2 family in this process. Comparison between physiological ligand and anti-Fas antibodies revealed that only extensive Fas aggregation, by membrane bound FasL or aggregated soluble FasL consistently triggered apoptosis, whereas antibodies could act as death agonists or antagonists. Studies on Fas signaling in cell lines and primary cells from transgenic mice revealed that FADD/MORT1 and caspase-8 were required for apoptosis. In contrast, Bcl-2 or Bcl-x_L did not block FasL-induced apoptosis in lymphocytes or hepatocytes, demonstrating that signaling for cell death induced by Fas and the pathways to apoptosis regulated by the Bcl-2 family are distinct.

Footnotes

↵ ‡ Present address: Department of Immunology and Oncology, Centro Nacional de Biotecnologia-CSIC Universidad Autonoma Campus de Cantoblanco, 28049 Madrid, Spain.
↵ ‖ To whom reprint requests should be addressed at: The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria 3050, Australia. E-mail: strasser{at}wehi.edu.au.
Abbreviations:

DD,

death domain;

TNF,

tumor necrosis factor