The JWA gene is functionally responsive to environmental oxidative stresses through its nuclear factor I binding site

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Oxidative stress has been suggested to be one of the major sources of DNA damage, and is believed to be a mediator for a variety of diseases, including cancer and chronic cardiovascular diseases. Our recent studies have shown that JWA gene is not only involved in chemically-induced directional differentiation of leukemia cell lines, but also responds to environmental stress, such as heat shock and oxidative stress, and may play a role as an environmental responses. However, the underlying mechanisms, including structure-function relationship, are still unclear. In this study, we identified JWA as a novel environmental responsive gene, and elucidated the mechanisms involved in its transcriptional modulation, and its potential function as well. We found that the JWA gene is actively responsive to hydrogen peroxide (H₂O₂) and benzo[a]pyrene (B(a)P) exposure in a dose- and time-dependent manner. We also found that H₂O₂ radical is the main oxidative product responsible for B(a)P-induced JWA expression. We further successfully identified the fragment (-58/-28 bp) of JWA promoter is a major region functionally responsive to both H₂O₂ and B(a)P via a CCAAT element, which specifically binds to activated nuclear transcription factor I (NFI). Moreover, we demonstrated that knock-down JWA expression by its specific JWA siRNA significant enhanced H₂O₂- and B(a)P-induced DNA damage and apoptosis, suggesting that JWA provide a inhibitory effect on DNA damage and apoptosis caused by the oxidative stress. Taken together, our studies demonstrate for the first time the mechanisms underlying the transcriptionally responsive regulation of the JWA gene upon oxidative stress, indicating that JWA is a novel environmental response gene with inhibitory function of reactive oxygen species (ROS)-associated DNA damage and apoptosis.