Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis.
The Fas/APO-1 receptor is one of the major regulators of apoptosis. We report here that Fas/APO-1-mediated apoptosis requires the activation of a new class of cysteine proteases, including interleukin-1 beta-converting enzyme (ICE), which are homologous to the product of the Caenorhabditis elegans cell-death gene ced-3 (refs 11, 12). Triggering of Fas/APO-1 rapidly stimulated the proteolytic activity of ICE. Overexpression of ICE, achieved by electroporation and microinjection, strongly potentiated Fas/APO-1-mediated cell death. In addition, inhibition of ICE activity by protease inhibitors, as well as by transient expression of the pox virus-derived serpin inhibitor CrmA or an antisense ICE construct, substantially suppressed Fas/APO-1-triggered cell death. We conclude that activation of ICE or an ICE-related protease is a critical event in Fas/APO-1-mediated cell death.
Los
M
M
Division of Immunochemistry, German Cancer Research Center, Heidelberg.
Van de Craen
M
M
Penning
L C
LC
Schenk
H
H
Westendorp
M
M
Baeuerle
P A
PA
Dröge
W
W
Krammer
P H
PH
Fiers
W
W
Schulze-Osthoff
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D029742:Caenorhabditis elegans Proteins; D020170:Caspase 1; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D016373:DNA, Antisense / Q000378:metabolism; D004789:Enzyme Activation; D015801:Helminth Proteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D015843:Serpins / Q000502:physiology; D014162:Transfection; D014764:Viral Proteins; D019014:fas Receptor
D000954:Antigens, Surface; D029742:Caenorhabditis elegans Proteins; D016373:DNA, Antisense; D015801:Helminth Proteins; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans; D020170:Caspase 1