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J. Biol. Chem., Vol. 282, Issue 31, 22307-22314, August 3, 2007

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Induction of Apoptosis Is Driven by Nuclear Retention of Protein Kinase C^*

Tracie A. DeVries-Seimon, Angela M. Ohm, Michael J. Humphries, and Mary E. Reyland^¶1

From the Department of Craniofacial Biology, School of Dentistry, and ^¶Department of Cell and Developmental Biology, School of Medicine, University Colorado Health Sciences Center, Aurora, Colorado 80045 and the Department of Medicine, Columbia University, New York, New York 10032

Protein kinase C (PKC) mediates apoptosis downstream of many apoptotic stimuli. Because of its ubiquitous expression, tight regulation of the proapoptotic function of PKC is critical for cell survival. Full-length PKC is found in all cells, whereas the catalytic fragment of PKC, generated by caspase cleavage, is only present in cells undergoing apoptosis. Here we show that full-length PKC transiently accumulates in the nucleus in response to etoposide and that nuclear translocation precedes caspase cleavage of PKC. Nuclear PKC is either cleaved by caspase 3, resulting in accumulation of the catalytic fragment in the nucleus, or rapidly exported by a Crm1-sensitive pathway, thereby assuring that sustained nuclear accumulation of PKC is coupled to caspase activation. Nuclear accumulation of PKC is necessary for caspase cleavage, as mutants of PKC that do not translocate to the nucleus are not cleaved. However, caspase cleavage of PKC per se is not required for apoptosis, as an uncleavable form of PKC induces apoptosis when retained in the nucleus by the addition of an SV-40 nuclear localization signal. Finally, we show that kinase negative full-length PKC does not translocate to the nucleus in apoptotic cells but instead inhibits apoptosis by blocking nuclear import of endogenous PKC. These studies demonstrate that generation of the PKC catalytic fragment is a critical step for commitment to apoptosis and that nuclear import and export of PKC plays a key role in regulating the survival/death pathway.

Received for publication, May 3, 2007 , and in revised form, June 8, 2007.

^* This work was supported by National Institutes of Health Grant DE015648 (to M. E. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Craniofacial Biology, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Ave., mail stop 8120, P. O. Box 6511, Aurora, CO 80045. Tel.: 303-724-4572; Fax: 303-724-4580; E-mail: Mary.Reyland{at}uchsc.edu.

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