Protein kinase C (PKC) fulfills a central role in the decision of cell fate in keratinocytes. Both PKCdelta and PKCeta induce growth inhibition and differentiation of normal human keratinocytes (NHK). Here we show that PKCdelta and PKCeta play opposite roles in UVB-induced apoptosis in NHK. PKCdelta enhanced UVB-induced caspase-3 activity, while overexpression of PKCeta reduced it. In keeping with these observations, the dominant negative mutant of PKCdelta significantly inhibited the activation of caspase-3, whereas dominant negative PKCeta increased it in a dose (MOI)-dependent manner. Unlike PKCdelta, cleavage and translocation to mitochondria of PKCeta were not observed, resulting in no detection of cytochorome c release. Furthermore, UV-induced activation of p38 MAP kinase, which suppressed the caspase-3 activity in NHK, was blocked by dominant negative PKCeta. These findings suggest that PKCeta negatively regulates UV-induced apoptosis through its localization, resistance to cleavage, and the p38 MAPK pathway. (C) 2003 Elsevier Science (USA). All rights reserved.