Abstract
Our previous studies indicated that JWA plays an important role in DNA damage repair, cell migration, and regulation of MAPKs. In this study, we investigated the role of JWA in chemical carcinogenesis using conditional JWA knockout (JWA Δ2/Δ2) mice and two-stage model of skin carcinogenesis. Our results indicated that JWA Δ2/Δ2 mice were resistant to the development of skin papillomas initiated by 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In JWA Δ2/Δ2 mice, the induction of papilloma was delayed, and the tumor number and size were reduced. In primary keratinocytes from JWA Δ2/Δ2 mice, DMBA exposure induced more intensive DNA damage, while TPA-promoted cell proliferation was reduced. The further mechanistic studies showed that JWA deficiency blocked TPA-induced activation of MAPKs and its downstream transcription factor Elk1 both in vitro and in vivo. JWA Δ2/Δ2 mice are resistance to tumorigenesis induced by DMBA/TPA probably through inhibition of transcription factor Elk1 via MAPKs. These results highlight the importance of JWA in skin homeostasis and in the process of skin tumor development.
Highlights
Viable cells suffer spontaneous DNA damage or genotoxic agent-induced DNA damages
Our results demonstrate that JWA deletion enhanced cellular DNA damage induced by DMBA at first stage, attenuated tumor incidence induced by TPA at second stage and probably via inactivation of MAPK pathway
Exon2 of JWA was floxed with Loxp site (JWAL), after Cre mediated recombination, the exon2 was deleted (JWAD2) (Fig. 1A)
Summary
Viable cells suffer spontaneous DNA damage or genotoxic agent-induced DNA damages. a network of DNA surveillance systems has developed in the cells that monitor and coordinate cell cycle progression with repair of damaged DNA to maintain genome integrity. MAPK (Mitogen-activated protein kinase) pathways are involved in the signal transduction of a wide variety of extracellular stimuli [5,6,7]. There are three such classical pathways that activate different MAPK classes, known as ERK (extracellular signal regulated kinase), JNK (Jun N-terminal kinase) and p38, each pathway evokes distinct biological responses. The MEK/ ERK pathway is activated by mitogenic stimuli and plays an important role in cell proliferation and differentiation. Activated ERK phosphorylates and activates its targets such as the transcription factor Elk (Ets-like transcription factor-1), member of ETS oncogene family. Activated Elk organizes ternary complex factor with serum response factor and binds to the serum response element of the promoter of the target genes (e.g. c-fos) and enhances their transcription [8,9,10]
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