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 development 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 dominant negative atypical PKCs (aPKCs). Here we investigated the role of aPKC in UV‐induced activation of mitogen activated protein (MAP) kinase family members which are considered to be the mediators of AP‐1 activation. We found that UV radiation led to translocation of protein kinase C (PKC) ζ and activation of MAP kinase family members as well as an increase of AP‐1–dependent transcription activation at the same dose range. Pretreatment of cells or mouse skin with antisense oligonucleotides of PKCζ impaired UV‐induced 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 p38 kinases in JB6 cells. In contrast, no significant inhibition of AP‐1 activation and MAP kinase activation were observed in cells treated with sense oligonucleotides of PKCζ. Furthermore, overexpression of a dominant negative mutant of PKCλ/ι specifically inhibited activation of extracellular signal–regulated protein kinases (ERKs) but not of c‐jun N‐terminal kinases (JNKs) nor p38 kinases induced by UV radiation. These results demonstrated that inhibition of aPKC impairs UV‐induced AP‐1 activation via suppression of ERKs activation but not of JNKs or p38 kinase activation. Mol. Carcinog. 27:65–75, 2000. © 2000 Wiley‐Liss, Inc.