Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases
Yao, S.L.; McKenna, K.A.; Sharkis, S.J.; Bedi, A.
Cancer Research 56(20): 4551-4555
1996
ISSN/ISBN: 0008-5472 PMID: 8840958 Document Number: 458441
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 1-beta-converting enzyme (ICE) and CPP32-beta, members of a family of cysteine proteases that are evolutionarily conserved determinants of cell death. We report here that Fast APO-1-triggered apoptosis involves ICE-mediated activation of p34-cdc2 kinase. Ligation of the Fas receptor resulted in the rapid stimulation of ICE proteolytic activity and activation of p34-cdc2 kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala-Asp-chloromethylketone) or CPP32-beta (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas and body-mediated activation of p34-cdc2 and inhibited apoptosis. Inhibition of p34-cdc2 activity by transient overexpression of a dominant-negative cdr-2 construct or human WEE1 kinase inhibited Fas-mediated apoptosis. These results suggest that activation of p34-cdc2 kinase is a critical determinant of cell death mediated by Fas and ICE family proteases.