Protein kinase C (PKC)delta plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKC delta generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKC delta isoform named PKC delta IX (Genebank Accession No. HQ840432). PKC delta IX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKC delta. PKC delta IX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKC delta IX provided a possibility that this PKC delta isozyme functions as a novel dominant-negative form for PKC delta due to its lack of the ATP-binding domain that is required for the kinase activity of PKC delta. Indeed, overexpression of PKC delta IX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKC delta IX protein could competitively inhibit the kinase activity of PKC delta. We conclude that PKC delta IX can function as a natural dominant-negative inhibitor of PKC delta in vivo. (C) 2011 Published by Elsevier Inc.