Nature 376, 37 - 43 (06 July 2002); doi:10.1038/376037a0

Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis

Donald W. Nicholson^*, Ambereen Ali^*, Nancy A. Thornberry^†, John P. Vaillancourt^*, Connie K. Ding^‡, Michel Gallant^§, Yves Gareau^§, Patrick R. Griffin^‡, Marc Labelle^§, Yuri A. Lazebnik, Neil A. Munday^*, Sayyaparaju M. Raju^‡, Mark E. Smulson^¶, Ting-Ting Yamin^‡, Violeta L. Yu^* & Douglas K. Miller^‡

Departments of ^* Biochemistry and Molecular Biology, and ^§ Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, H9R 4P8 Canada
Departments of ^† Biochemistry and ^‡ Inflammation Research, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA
Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York 11724, USA
^¶ Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington DC, USA

The protease responsible for the cleavage of poly(ADP-ribose) polymerase and necessary for apoptosis has been purified and characterized. This enzyme, named apopain, is composed of two subunits of relative molecular mass (M _r) 17K and 12K that are derived from a common proenzyme identified as CPP32. This proenzyme is related to interleukin-l-converting enzyme (ICE) and CED-3, the product of a gene required for programmed cell death in Caenorhabditis elegans. A potent peptide aldehyde inhibitor has been developed and shown to prevent apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.

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