A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis.
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.
D'Costa
A M
AM
Division of Molecular and Cellular Biochemistry, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA.
Denning
M F
MF
D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000037:antagonists & inhibitors; D015536:Down-Regulation; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology / Q000528:radiation effects; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects*
D061945:Caspase Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases