Protein kinase Cdelta is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes.
The elimination of ultraviolet (UV) radiation-damaged keratinocytes via apoptosis is an important mechanism for the protection of the skin from sunlight, an ubiquitous environmental carcinogen. Due to the pleiotropic nature of UV radiation, the molecular mechanisms of UV-induced apoptosis are poorly understood. Protein kinase C (PKC) is a family of enzymes critically involved in the regulation of differentiation in the epidermis, and is associated with the induction of apoptosis by ionizing radiation in other cell types. In normal human keratinocytes, the induction of apoptosis by UV exposure correlated with generation of the catalytic domain of PKCdelta in the soluble fraction. In contrast, phorbol ester 12-O-tetradecanoylphorbol-13-acetate caused translocation of PKCdelta from the soluble to the particulate fraction without inducing apoptosis. The effect of UV radiation on PKCdelta was isoform specific, as UV exposure did not stimulate the cleavage, or effect the subcellular distribution of any other PKC isoform. The soluble, catalytic domain of PKCdelta induced by UV exposure was associated with an increase in soluble PKCdelta activity. Proteases of the caspase family are activated during UV-induced apoptosis. Inhibition of caspases blocked the UV-induced cleavage of PKCdelta and apoptosis. In addition, inhibition of PKC activity specifically inhibited UV-induced apoptosis of keratinocytes, without affecting the G0/G1 cell cycle block induced by UV exposure. These results indicate that PKC activation is involved in the UV-induced death effector pathway of keratinocytes undergoing apoptosis, and defines a novel role for this enzyme in epidermal homeostasis.
Denning
M F
MF
Department of Pathology and the Cardinal Bernardin Cancer Center, Skin Cancer Research Program, Loyola University Medical Center, Maywood, Illinois 60153, USA. mdennin@luc.edu
Wang
Y
Y
Nickoloff
B J
BJ
Wrone-Smith
T
T
D017209:Apoptosis / Q000528:radiation effects*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D016193:G1 Phase; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology / Q000528:radiation effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D014466:Ultraviolet Rays
D007527:Isoenzymes; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D003546:Cysteine Endopeptidases