c-Jun N-Terminal Kinase 1 Phosphorylates Myt1 To Prevent UVA-Induced Skin Cancer

The c-Jun N-terminal kinase (JNK) signaling pathway is known to mediate both survival and apoptosis of tumor cells. Although JNK1 and JNK2 have been shown to differentially regulate the development of skin cancer, the underlying mechanistic basis remains unclear. Here, we demonstrate that JNK1, but not JNK2, interacts with and phosphorylates Myt1 ex vivo and in vitro. UVA induces substantial apoptosis inJNK wild-type (JNK +/+ ) orJNK2 -deficient (JNK2 −/− ) mouse embryonic fibroblasts but has no effect on JNK1-deficient (JNK1 −/− ) cells. In addition, UVA-induced caspase-3 cleavage and DNA fragmentation were suppressed by the knockdown of humanMyt1 in skin cancer cells.JNK1 deficiency results in suppressed Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA irradiation. In contrast, the absence ofJNK2 induces Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA. The overexpression ofJNK1 withMyt1 promotes cellular apoptosis during the early embryonic development ofXenopus laevis , whereas the presence ofJNK2 reduces the phenotype of Myt1-induced apoptotic cell death. Most importantly,JNK1 −/− mice developed more UVA-induced papillomas than eitherJNK +/+ orJNK2 −/− mice, which was associated with suppressed Myt1 phosphorylation and decreased caspase-3 cleavage. Taken together, these data provide mechanistic insights into the distinct roles of the different JNK isoforms, specifically suggesting that the JNK1-mediated phosphorylation of Myt1 plays an important role in UVA-induced apoptosis and the prevention of skin carcinogenesis.