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Volume 271, Number 46, Issue of November 15, 1996 pp. 29335-29341
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Heteronuclear Ribonucleoproteins C1 and C2, Components of the Spliceosome, Are Specific Targets of Interleukin 1-converting Enzyme-like Proteases in Apoptosis

(Received for publication, August 9, 1996)

Nigel Waterhouse ^§ , Sharad Kumar ^¶ , Qizhong Song , Phil Strike , Lindsay Sparrow , Gideon Dreyfuss ^** , Emad S. Alnemri , Gerald Litwack , Martin Lavin ^§ and Dianne Watters

From the  Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, P. O. Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia, ^§ Department of Surgery, University of Queensland, St. Lucia, Queensland 4072, Australia, ^¶ The Hanson Centre for Cancer Research, P. O. Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia,  Commonwealth Scientific and Industrial Research Organization, Division of Biomolecular Engineering, Parkville, Victoria 3052, Australia, ^** Howard Hughes Medical Institute Research Laboratories, University of Pennsylvania School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania 19104-6148, and  Department of Pharmacology and the Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Apoptosis induced by a variety of agents results in the proteolytic cleavage of a number of cellular substrates by enzymes related to interleukin 1-converting enzyme (ICE). A small number of substrates for these enzymes have been identified to date, including enzymes involved in DNA repair processes: poly(ADP-ribose) polymerase and DNA-dependent protein kinase. We describe here for the first time the specific cleavage of the heteronuclear ribonucleoproteins (hnRNPs) C1 and C2 in apoptotic cells induced to undergo apoptosis by a variety of stimuli, including ionizing radiation, etoposide, and ceramide. No cleavage was observed in cells that are resistant to apoptosis induced by ionizing radiation. Protease inhibitor data implicate the involvement of an ICE-like protease in the cleavage of hnRNP C. Using recombinant ICE-like proteases and purified hnRNP C proteins in vitro, we show that the C proteins are cleaved by Mch3 and CPP32 and, to a lesser extent, by Mch2, but not by ICE, Nedd2, Tx, or the cytotoxic T-cell protease granzyme B. The results described here demonstrate that the hnRNP C proteins, abundant nuclear proteins thought to be involved in RNA splicing, belong to a critical set of protein substrates that are cleaved by ICE-like proteases during apoptosis.

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