Inhibition of atypical PKC blocks ultraviolet-induced AP-1 activation by specifically inhibiting ERKs activation

Since ultraviolet (UV) radiation is a major etiologic factor in the develop ment of human skin cancers, investigating the signal transduction pathways initiated by UV radiation may help with the understanding of the molecular mechanisms of UV-induced carcinogenesis. Our previous studies demonstrated that UV-induced activator protein-1 (AP-1) activation is blocked by dominan t negative atypical PKCs (aPKCs). Here we investigated the role of aPKC in UV-induced activation of mitogen activated protein (MAP) kinase family memb ers which are considered to be the mediators of AP-1 activation. We found t hat UV radiation led to translocation of protein kinase C (PKC) zeta and ac tivation of MAP kinase family members as well as an increase of AP-1-depend ent transcription activation at the same dose range. Pretreatment of cells or mouse skin with antisense oligonucleotides of PKC zeta impaired UV-induc ed activation of AP-1 in JB6 cells as well as in AP-1-luciferase transgenic mice. it also inhibited UV-induced activation of ERKs but not of JNK and p 38 kinases in JB6 cells. In contrast, no significant inhibition of AP-1 act ivation and MAP kinase activation were observed in cells treated with sense oligonucleotides of PKC zeta. Furthermore, overexpression of a dominant ne gative mutant of PKC lambda/iota specifically inhibited activation of extra cellular signal-regulated protein kinases (ERKs) but not of c-jun N-termina l kinases (JNKs) nor p38 kinases induced by UV radiation. These results dem onstrated that inhibition of aPKC impairs UV-induced AP-1 activation via su ppression of ERKs activation but not of JNKs or p38 kinase activation. (C) 2000 Wiley-Liss, Inc.