REQUIREMENT OF P34(CDC2) KINASE FOR APOPTOSIS MEDIATED BY THE FAS APO-1 RECEPTOR AND INTERLEUKIN 1-BETA-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 apoptoti c signal that requires activation of interleukin 1 beta-converting enz yme (ICE) and CPP32 beta, members of a family of cysteine proteases th at are evolutionarily conserved determinants of cell death. We report here that Fas/APO-1-triggered apoptosis involves ICE-mediated activati on of p34(cdc2) kinase. Ligation of the Fas receptor resulted in the r apid stimulation of ICE proteolytic activity and activation of p34(cdc 2) kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala -Asp-chloromethylketone) or CPP32 beta (Acetyl-Asp-Glu-Val-Asp-aldehyd e) prevented the anti-Fas antibody-mediated activation of p34(cdc2) an d inhibited apoptosis. Inhibition of p34(cdc2) activity by transient o verexpression of a dominant-negative cdc2 construct or human WEE1 kina se inhibited Fas-mediated apoptosis. These results suggest that activa tion of p34(cdc2) kinase is a critical determinant of cell death media ted by Fas and ICE family proteases.