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J. Biol. Chem., Vol. 275, Issue 24, 18476-18481, June 16, 2000

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Proteolytic Cleavage and Activation of Protein Kinase C µ by Caspase-3 in the Apoptotic Response of Cells to 1--D-Arabinofuranosylcytosine and Other Genotoxic Agents^*

Kazuya Endo^§, Eiji Oki^§, Verena Biedermann, Hiromi Kojima, Kiyotsugu Yoshida, Franz-Josef Johannes^¶, Donald Kufe, and Rakesh Datta

From the  Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 and ^¶ Institute of Cell Biology and Immunology, University of Stuttgart, Germany

Protein kinase C (PKC) µ is a novel member of the PKC family that differs from the other isozymes in structural and biochemical properties. The precise function of PKCµ is not known. The present studies demonstrate that PKCµ is cleaved during apoptosis induced by 1--D-arabinofuranosylcytosine (ara-C) and other genotoxic agents. PKCµ cleavage is blocked in cells that overexpress the anti-apoptotic Bcl-x_L protein or the baculovirus p35 protein. Our results demonstrate that PKCµ is cleaved by caspase-3 at the CQND³⁷⁸S site. Cleavage of PKCµ is associated with release of the catalytic domain and activation of its kinase function. We also show that, unlike the cleaved fragments of PKC and , overexpression of the PKCµ catalytic domain is not lethal. Cells stably expressing the catalytic fragment of PKCµ, however, are more sensitive to apoptosis induced by genotoxic stress. In addition, expression of the caspase-resistant PKCµ mutant partially inhibits DNA damage-induced apoptosis. These findings demonstrate that PKCµ is cleaved by caspase-3 and that expression of the catalytic domain sensitizes cells to the cytotoxic effects of ara-C and other anticancer agents.

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