Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases.
The induction of apoptosis by the Fas/APO-1 receptor is important for T-cell-mediated cytotoxicity and down-regulation of immune responses. Binding of Fas ligand to the Fas/APO-1 receptor transduces an apoptotic signal that requires activation of interleukin 1beta-converting enzyme (ICE) and CPP32beta, members of a family of cysteine proteases that are evolutionarily conserved determinants of cell death. We report here that Fas/APO-1-triggered apoptosis involves ICE-mediated activation of p34cdc2 kinase. Ligation of the Fas receptor resulted in the rapid stimulation of ICE proteolytic activity and activation of p34cdc2 kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala-Asp-chloromethylketone) or CPP32beta (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas antibody-mediated activation of p34cdc2 and inhibited apoptosis. Inhibition of p34cdc2 activity by transient overexpression of a dominant-negative cdc2 construct or human WEE1 kinase inhibited Fas-mediated apoptosis. These results suggest that activation of p34cdc2 kinase is a critical determinant of cell death mediated by Fas and ICE family proteases.
Yao
S L
SL
The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
McKenna
K A
KA
Sharkis
S J
SJ
Bedi
A
A
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis*; D018110:Receptors, Lipoprotein / Q000502:physiology; D014162:Transfection; D019014:fas Receptor / Q000276:immunology*
D018110:Receptors, Lipoprotein; D019014:fas Receptor; D011494:Protein Kinases; D016203:CDC2 Protein Kinase; D003546:Cysteine Endopeptidases; D020170:Caspase 1