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

Kazuya Endo, Eiji Oki, Verena Biedermann, Hiromi Kojima, Kiyotsugu Yoshida, Franz Josef Johannes, Donald Kufe, Rakesh Datta

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93 Citations (Scopus)

Abstract

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-β-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 CQND378 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 PKCδ and θ, 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.

Original languageEnglish
Pages (from-to)18476-18481
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number24
DOIs
Publication statusPublished - Jun 16 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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