Protein kinase Cδ 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 PKC delta in the soluble fraction. In contrast, phorbol ester 12-O-tetradecanoylphorbol-13-acetate caused translocation of PKC delta from the soluble to the particulate fraction without inducing apoptosis. The effect of UV radiation on PKC delta 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 PKC delta induced by UV exposure was associated with an increase in soluble PKC delta activity. Proteases of the caspase family are activated duping W-induced apoptosis. Inhibition of caspases blocked the W-induced cleavage of PKC delta and apoptosis. In addition, inhibition of PKC activity specifically inhibited UV-induced apoptosis of keratinocytes, without affecting the G(0)/G(1) cell cycle block induced by UV exposure. These results indicate that PKC activation is involved in the W-induced death effector pathway of keratinocytes undergoing apoptosis, and defines a novel role for this enzyme in epidermal homeostasis.