Identification of JWA as a novel functional gene responsive to environmental oxidative stress induced by benzo[a]pyrene and hydrogen peroxide.
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.
Chen
Rui
R
Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, People's Republic of China.
Qiu
Wen
W
Liu
Zulong
Z
Cao
Xingjiang
X
Zhu
Ting
T
Li
Aiping
A
Wei
Qingyi
Q
Zhou
Jianwei
J
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
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