title: Identification of JWA as a novel functional gene responsive to environmental oxidative stress induced by benzo[a]pyrene and hydrogen peroxide.
abstract: Oxidative stress has been implicated as one of the primary mechanisms inducing DNA damage and believed to mediate aging and progression of numerous age-related diseases, including cancer. JWA, a gene previously described to mediate differentiation of leukemic cells, is also involved in cellular responses to environmental exposures linked to heat shock and chemical-mediated oxidative stresses. However, the precise pathways and mechanisms underlying these phenomena remain to be resolved. Our studies demonstrated that H(2)O(2) is the primary oxidative product responsible for benzo[a]pyrene (B[a]P)-induced JWA expression, and knockdown of JWA elevates H(2)O(2) (100 microM)- and B[a]P (100 microM)-induced DNA damage. In oxidative stress cell culture models, JWA was upregulated. JWA expression regulated a parallel rise in the base excision repair protein XRCC1 but a reduction in PARP1 in response to H(2)O(2)-induced DNA damage. Furthermore, we found that both H(2)O(2) and B[a]P exposure activated nuclear transcription factor I (NFI) in NIH-3T3 cells, which specifically bound to the CCAAT element in the JWA proximal promoter (-58/-28 bp) and thereby induced JWA expression. Consistently siRNA mediated a knockdown of NFI, which prevented JWA induction. These findings indicate that JWA may serve as a novel environmental stress sensor to protect cells against reactive oxygen species-associated DNA damage.
authors.affiliation: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.forename: Zulong
authors.initials: Z
authors.lastname: Liu
authors.forename: Xingjiang
authors.initials: X
authors.lastname: Cao
authors.forename: Ting
authors.initials: T
authors.lastname: Zhu
authors.forename: Aiping
authors.initials: A
authors.lastname: Li
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004249:DNA Damage; D004777:Environment; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D026901:Membrane Transport Proteins; D051379:Mice; D008969:Molecular Sequence Data; D051839:NFI Transcription Factors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C464502:Arl6ip5 protein, mouse; D023081:CCAAT-Binding Factor; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D051839:NFI Transcription Factors; D001564:Benzo(a)pyrene; D006861:Hydrogen Peroxide