ets-1 is transcriptionally up-regulated by H2O2 via an antioxidant response element

doi:10.1096/fj.05-4401fje

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ets-1 is transcriptionally up-regulated by H₂O₂ via an antioxidant response element

Leigh A. Wilson, Adam Gemin, Raissa Espiritu, and Gurmit Singh

E-mail contact: gurmit.singh{at}hrcc.on.ca

Expression of the transcription factor Ets-1 is increasingly associated with the progression of several human cancers. A tumor-derived factor is expected to be involved in the inappropriate up-regulation of ets-1 in tumor and surrounding cells. A link between hydrogen peroxide (H₂O₂) and increased Ets-1 expression has also been suggested, leading to the proposal that this reactive oxygen species (ROS) may be an important factor in directly regulating the expression of ets-1 in tumor cells. Ets-1 expression in response to H₂O₂ was examined in an ovarian carcinoma cell model, and the genes promoter region was analyzed in order to identify putative elements involved in redox responsiveness. The up-regulation of Ets-1 by H₂O₂ was confirmed in the cells tested. Luciferase assays using constructs generated to test the contribution of specific promoter elements indicated that an antioxidant response element (ARE) is primarily involved in the H₂O₂-mediated induction. Gel shift analysis confirmed the increased binding of an Nrf2 containing protein complex to the ets-1 ARE after H₂O₂ treatment. This study has delineated a key element involved in the transcriptional regulation of ets-1 under basal and induced conditions. Ets-1 has obvious deleterious effects in many cancer cells, and thus, the identification of this regulatory pathway has provided possible targets for manipulating its expression.

Key words: tumor-derived factor • reactive oxygen species • gel shift analysis

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