J. Exp. Med.
© The Rockefeller University Press
0022-1007/96/12/2399/06 $2.00
Volume 184 December 1996 2399-2404

BRIEF DEFINITIVE REPORT:
Proteolytic Activation of Protein Kinase C  by an ICE/CED 3-like Protease Induces Characteristics of Apoptosis

By Tariq Ghayur,^* Margaret Hugunin,^* Robert V. Talanian,^* Sheldon Ratnofsky,^* Christopher Quinlan,^* Yutaka Emoto, Pramod Pandey, Rakesh Datta, Yinyin Huang, Surender Kharbanda, Hamish Allen,^* Robert Kamen,^* Winnie Wong,^* and Donald Kufe

From ^* BASF Bioresearch Corporation, Worcester, Massachusetts 01605; and  Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

Recent studies have shown that protein kinase C (PKC)  is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKC cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKC is cleaved at DMQD₃₃₀N to a catalytically active fragment by the cysteine protease CPP32. The results also demonstrate that overexpression of the catalytic kinase fragment in cells is associated with chromatin condensation, nuclear fragmentation, induction of sub-G1 phase DNA and lethality. By contrast, overexpression of full-length PKC or a kinase inactive PKC fragment had no detectable effect. The findings suggest that proteolytic activation of PKC by a CPP32-like protease contributes to phenotypic changes associated with apoptosis.

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• Reyland, M. E., Anderson, S. M., Matassa, A. A., Barzen, K. A., Quissell, D. O. (1999). Protein Kinase C delta  Is Essential for Etoposide-induced Apoptosis in Salivary Gland Acinar Cells. J. Biol. Chem. 274: 19115-19123 [Abstract] [Full Text]  
• Khwaja, A., Tatton, L. (1999). Caspase-Mediated Proteolysis and Activation of Protein Kinase Cdelta Plays a Central Role in Neutrophil Apoptosis. Blood 94: 291-301 [Abstract] [Full Text]  
• Marshall, W. L., Yim, C., Gustafson, E., Graf, T., Sage, D. R., Hanify, K., Williams, L., Fingeroth, J., Finberg, R. W. (1999). Epstein-Barr Virus Encodes a Novel Homolog of the bcl-2 Oncogene That Inhibits Apoptosis and Associates with Bax and Bak. J. Virol. 73: 5181-5185 [Abstract] [Full Text]  
• Galvin, J. P., Spaeny-Dekking, L. H. A., Wang, B., Seth, P., Hack, C. E., Froelich, C. J. (1999). Apoptosis Induced by Granzyme B-Glycosaminoglycan Complexes: Implications for Granule-Mediated Apoptosis In Vivo. J. Immunol. 162: 5345-5350 [Abstract] [Full Text]  
• Frutos, S., Moscat, J., Diaz-Meco, M. T. (1999). Cleavage of zeta PKC but Not lambda /iota PKC by Caspase-3 during UV-induced Apoptosis. J. Biol. Chem. 274: 10765-10770 [Abstract] [Full Text]  
• Huang, Y., Nakada, S., Ishiko, T., Utsugisawa, T., Datta, R., Kharbanda, S., Yoshida, K., Talanian, R. V., Weichselbaum, R., Kufe, D., Yuan, Z.-M. (1999). Role for Caspase-Mediated Cleavage of Rad51 in Induction of Apoptosis by DNA Damage. Mol. Cell. Biol. 19: 2986-2997 [Abstract] [Full Text]  
• Pandey, P., Avraham, S., Place, A., Kumar, V., Majumder, P. K., Cheng, K., Nakazawa, A., Saxena, S., Kharbanda, S. (1999). Bcl-xL Blocks Activation of Related Adhesion Focal Tyrosine Kinase/Proline-rich Tyrosine Kinase 2 and Stress-activated Protein Kinase/c-Jun N-terminal Protein Kinase in the Cellular Response to Methylmethane Sulfonate. J. Biol. Chem. 274: 8618-8623 [Abstract] [Full Text]  
• Denning, M. F., Wang, Y., Nickoloff, B. J., Wrone-Smith, T. (1998). Protein Kinase Cdelta Is Activated by Caspase-dependent Proteolysis during Ultraviolet Radiation-induced Apoptosis of Human Keratinocytes. J. Biol. Chem. 273: 29995-30002 [Abstract] [Full Text]  
• Bharti, A., Kraeft, S.-K., Gounder, M., Pandey, P., Jin, S., Yuan, Z.-M., Lees-Miller, S. P., Weichselbaum, R., Weaver, D., Chen, L. B., Kufe, D., Kharbanda, S. (1998). Inactivation of DNA-Dependent Protein Kinase by Protein Kinase Cdelta : Implications for Apoptosis. Mol. Cell. Biol. 18: 6719-6728 [Abstract] [Full Text]  
• Martins, L. M., Kottke, T. J., Kaufmann, S. H., Earnshaw, W. C. (1998). Phosphorylated Forms of Activated Caspases Are Present in Cytosol From HL-60 Cells During Etoposide-Induced Apoptosis. Blood 92: 3042-3049 [Abstract] [Full Text]  
• Resnick, M. S., Kang, B.-S., Luu, D., Wickham, J. T., Sando, J. J., Hahn, C. S. (1998). Differential Downstream Functions of Protein Kinase Ceta and -theta in EL4 Mouse Thymoma Cells. J. Biol. Chem. 273: 27654-27661 [Abstract] [Full Text]  
• Simizu, S., Takada, M., Umezawa, K., Imoto, M. (1998). Requirement of Caspase-3(-like) Protease-mediated Hydrogen Peroxide Production for Apoptosis Induced by Various Anticancer Drugs. J. Biol. Chem. 273: 26900-26907 [Abstract] [Full Text]  
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