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  • The EMBO Journal (2002) 21, 6050 - 6060
  • doi:10.1093/emboj/cdf606

Nuclear import of PKCdelta is required for apoptosis: identification of a novel nuclear import sequence

Tracie A. DeVries1, Margaret C. Neville2,3 and Mary E. Reyland2,4

  1. Department of Pathology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
  2. Department of Cell and Structural Biology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
  3. Department of Physiology and Biophysics, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
  4. Department of Craniofacial Biology, School of Dentistry, University of Colorado Health Sciences Center, Denver, CO 80262, USA

Correspondence to:

Mary E. Reyland, E-mail: Mary.Reyland@UCHSC.edu

Received 26 March 2002; Accepted 23 September 2002; Revised 6 August 2002

We have shown previously that protein kinase Cdelta (PKCdelta) is required for mitochondrial-dependent apoptosis. Here we show that PKCdelta is imported into the nucleus of etoposide-treated cells, that nuclear import is required for apoptosis and that it is mediated by a nuclear localization signal (NLS) in the C-terminus of PKCdelta. Mutation of the caspase cleavage site of PKCdelta inhibits nuclear accumulation in apoptotic cells, indicating that caspase cleavage facilitates this process. Expression of the PKCdelta catalytic fragment (CFdelta) in transfected cells results in nuclear localization and apoptosis. We show that the PKCdelta NLS is required for nuclear import of both full-length PKCdelta and CFdelta, and drives nuclear localization of a multimeric green fluorescent protein. Mutations within the NLS of CFdelta prevent nuclear accumulation and block apoptosis. Conversely, nuclear expression of a kinase-negative catalytic fragment (KN-CFdelta) protects cells from etoposide-induced apoptosis. Mutation of the NLS blocks the ability of KN-CFdelta to protect against etoposide-induced apoptosis. These results indicate that PKCdelta regulates an essential nuclear event(s) that is required for initiation of the apoptotic pathway.

  • Keywords:

    • apoptosis,
    • DNA damage,
    • nuclear localization,
    • protein kinase Cdelta