title: JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice.
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.
authors.affiliation: Department of Molecular Cell Biology & Toxicology, the Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Gong
authors.forename: Yaowei
authors.initials: Y
authors.lastname: Shi
authors.forename: Ze
authors.initials: Z
authors.lastname: Zhu
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhang
authors.forename: Aiping
authors.initials: A
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D006360:Heat-Shock Proteins; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D026901:Membrane Transport Proteins; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C464502:Arl6ip5 protein, mouse; D002273:Carcinogens; D002352:Carrier Proteins; C494113:Elk1 protein, mouse; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D018809:Proliferating Cell Nuclear Antigen; D050807:ets-Domain Protein Elk-1; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate