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Requirement of p34^cdc2 Kinase for Apoptosis Mediated by the Fas/APO-1 Receptor and Interleukin 1ß-converting Enzyme-related Proteases¹

The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287

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 1ß-converting enzyme (ICE) and CPP32ß, 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 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 CPP32ß (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas antibody-mediated activation of p34^cdc2 and inhibited apoptosis. Inhibition of p34^cdc2 activity by transient overexpression of a dominant-negative cdc2 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.

¹ A. B. is a recipient of a Jose Carreras American Society of Hematology Scholar Award, a Passano Physician Scientist Award, and grants from the American Cancer Society and the Wendy Will Case Cancer Fund.

² To whom requests for reprints should be addressed, at the Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-2813; Fax: (410) 955-1969.

Received 7/ 9/96. Accepted 8/26/96.

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