Affiliation:
1. College of Pharmacy, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
2. The Hormel Institute, University of Minnesota, Austin, Minnesota 55912
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
28 articles.
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