Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x(L).
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.
Huang
D C
DC
The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Vic 3050, Melbourne, Australia.
Hahne
M
M
Schroeter
M
M
Frei
K
K
Fontana
A
A
Villunger
A
A
Newton
K
K
Tschopp
J
J
Strasser
A
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D007152:Immunologic Capping; D008099:Liver / Q000166:cytology / Q000502:physiology; D008214:Lymphocytes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
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; D008562:Membrane Glycoproteins; D011498:Protein Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases