title: DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis in human embryo lung fibroblast cells.
abstract: When cells encounter genotoxic stress, sensors for DNA lesions stabilize and activate p53; the signals involved, however, are largely unclear. Inorganic arsenite is a ubiquitous environmental contaminant associated with an increased risk of lung and skin damage and cancer. Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure. Here, we find that, in human embryo lung fibroblast (HELF) cells, arsenite induces the activation of dependent protein kinase catalytic subunit (DNA-PKcs), which then phosphorylates and activates c-Jun N-terminal kinases 2 (JNK2), but not JNK1. As a positive regulator of p53, JNK2 binds to p53 and prevents p53 from murine double minute 2 (mdm2)-mediated, ubiquitin-proteasome-dependent degradation. Knockdown of DNA-PKcs/JNK2 signal pathway or p53 reduces apoptosis but elevates the DNA damage induced by a high level of arsenite. These results suggest that DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis.
authors.affiliation: Institute of Toxicology, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rongrong
authors.initials: R
authors.lastname: Jiang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Ling
authors.forename: Ying
authors.initials: Y
authors.lastname: Pang
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D002478:Cells, Cultured; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D020935:MAP Kinase Signaling System; D024101:Mitochondrial Proteins / Q000032:analysis; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018053:Arsenites; D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048056:Mitogen-Activated Protein Kinase 9; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C015001:arsenite