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Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis

Abstract

BINDING of Fas ligand or an agonistic anti-Fas antibody induces apoptosis in Fas-bearing cells1. The interleukin-lβ-converting enzyme (ICE) is a cysteine protease2 that is involved in apoptosis induced by various stimuli, including Fas-mediated apoptosis3–8. Several ICE homologues have been identified, and these are subdivided into three groups (ICE-, CPP32- and Ich-1-like pro-teases)9–18. We show here that specific inhibitors of ICE- or CPP32-like proteases can inhibit Fas-mediated apoptosis. Tran-sient ICE-like activity was found in the cytosolic fraction of Fas-activated cells, whereas ICE-dependent, CPP32-like activity gradually accumulated in the cytosol. Cell lysates from mouse lymphoma supplemented with either recombinant ICE or CPP32 induced apoptosis of nuclei. The CPP32 inhibitor inhibited ICE-or CPP32-induced apoptosis in the cell-free system, whereas the ICE-inhibitor only inhibited ICE-induced apoptosis. Cell extracts from thymocytes from ICE-null mice induced apoptosis in the cell-free system when it was supplemented with CPP32. These results indicate that Fas sequentially activates ICE- and CPP32-like proteases, and that downstream CPP32, together with a component(s) in the cytoplasm, causes apoptosis of nuclei.

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Enari, M., Talanian, R., Wrong, W. et al. Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature 380, 723–726 (1996). https://doi.org/10.1038/380723a0

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