Article ID Journal Published Year Pages File Type
1911854 Free Radical Biology and Medicine 2007 11 Pages PDF
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 H2O2 is the primary oxidative product responsible for benzo[a]pyrene (B[a]P)-induced JWA expression, and knockdown of JWA elevates H2O2 (100 μM)- and B[a]P (100 μM)-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 H2O2-induced DNA damage. Furthermore, we found that both H2O2 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.
Related Topics
Life Sciences Biochemistry, Genetics and Molecular Biology Ageing
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