Proteolytic cleavage and activation of protein kinase C μ by caspase-3 in the apoptotic response of cells to 1-β-D-arabinofuranosylcytosine and other genotoxic agents

Protein kinase C (PKC) mu is a novel member of the PKC family that differs from the other isozymes in structural and biochemical properties, The precise function of PKC mu is not known. The present studies demonstrate that PKC mu is cleaved during apoptosis induced by 1-beta-D-arabinofuranosylcytosine (ara C) and other genotoxic agents, PKC mu cleavage is blocked in cells that overexpress the anti-apoptotic Bcl-x(L) protein or the baculovirus p35 protein, Our results demonstrate that PKC mu is cleaved by caspase-3 at the CQND(378)S site. Cleavage of PKC mu is associated with release of the catalytic domain and activation of its kinase function. We also show that, unlike the cleaved fragments of PKC delta and theta, overexpression of the PKC mu catalytic domain is not lethal. Cells stably expressing the catalytic fragment of PKC mu, however, are more sensitive to apoptosis induced by genotoxic stress. In addition, expression of the caspase-resistant PKC mu mutant partially inhibits DNA damage-induced apoptosis, These findings demonstrate that PKC mu 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.