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 in JNK wild-type (JNK(+/+)) or JNK2-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 human Myt1 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 of JNK2 induces Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA. The overexpression of JNK1 with Myt1 promotes cellular apoptosis during the early embryonic development of Xenopus laevis, whereas the presence of JNK2 reduces the phenotype of Myt1-induced apoptotic cell death. Most importantly, JNK1(-/-) mice developed more UVA-induced papillomas than either JNK(+/+) or JNK2(-/-) 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.
Choi
Hong Seok
HS
College of Pharmacy, Chosun University, Dong-gu, Gwangju 501-759, South Korea.
Bode
Ann M
AM
Shim
Jung-Hyun
JH
Lee
Sung-Young
SY
Dong
Zigang
Z
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014982:Xenopus laevis
D004268:DNA-Binding Proteins; C078341:MYT1 protein, human; C489726:Myt1 protein, mouse; D014157:Transcription Factors; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3