PROTEIN-KINASE C-DELTA IS ACTIVATED BY CASPASE-DEPENDENT PROTEOLYSIS DURING ULTRAVIOLET RADIATION-INDUCED APOPTOSIS OF HUMAN KERATINOCYTES

The elimination of ultraviolet (UV) radiation-damaged keratinocytes vi a apoptosis is an important mechanism for the protection of the skin f rom sunlight, an ubiquitous environmental carcinogen. Due to the pleio tropic 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 t he epidermis, and is associated with the induction of apoptosis by ion izing radiation in other cell types. In normal human keratinocytes, th e 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 translocat ion of PKC delta from the soluble to the particulate fraction without inducing apoptosis. The effect of UV radiation on PKC delta was isofor m specific, as UV exposure did not stimulate the cleavage, or effect t he subcellular distribution of any other PKC isoform. The soluble, cat alytic domain of PKC delta induced by UV exposure was associated with an increase in soluble PKC delta activity. Proteases of the caspase fa mily 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 apoptos is 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 unde rgoing apoptosis, and defines a novel role for this enzyme in epiderma l homeostasis.