A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis

Cell Death Differ. 2005 Mar;12(3):224-32. doi: 10.1038/sj.cdd.4401558.

Abstract

Keratinocyte apoptosis induced by UV radiation is a major protective mechanism from skin photocarcinogenesis. The induction of apoptosis by UV radiation, as well as a variety of genotoxic stimuli, involves the activation of PKC-delta by caspase-3-mediated cleavage in its hinge region, thus generating a constitutively active catalytic fragment. To determine the role of PKC-delta cleavage in UV apoptosis signaling, we introduced a caspase-resistant PKC-delta mutant (D330A) into human keratinocytes by retrovirus transduction. Overexpression of PKC-delta(D330A) protected keratinocytes from UV-induced apoptosis and enhanced long-term survival. PKC-delta(D330A) partially prevented the release of cytochrome c from the mitochondria and the loss of Mcl-1, a key antiapoptotic protein downregulated during UV apoptosis. Thus, the cleavage and activation of PKC-delta are critical components of UV-induced apoptosis in human keratinocytes, and the inactivation of PKC-delta can promote the survival of keratinocytes exposed to UV radiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Catalytic Domain
  • Cell Survival
  • Cells, Cultured
  • Cytochromes c / antagonists & inhibitors
  • Down-Regulation
  • Enzyme Activation
  • Flow Cytometry
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Membrane Potentials
  • Mitochondria / physiology
  • Mitochondria / radiation effects
  • Mutation
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / biosynthesis
  • Protein Kinase C / biosynthesis
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase C-delta
  • Protein Transport
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Ultraviolet Rays / adverse effects*

Substances

  • Caspase Inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Cytochromes c
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta
  • CASP3 protein, human
  • Caspase 3
  • Caspases