ets‐1is transcriptionally up‐regulated by H₂O₂via an antioxidant response element

Abstract

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.

Analysis of Gene Expression Regulated by the ETV5 Transcription Factor in OV90 Ovarian Cancer Cells Identifies FOXM1 Overexpression in Ovarian Cancer

“…Interestingly, in tumor cells, ROS is an important factor that directly regulates the expression of ETS-1, the founder member of the ETS family of transcription factors (43,44). Likewise, H 2 O 2 is able to transcriptionally upregulate ETS-1 in ovarian cancer cells (45). There is also evidence that ETS-2, a closely related family member of ETS-1, is transcriptionally upregulated by H 2 O 2 treatment in NIH3T3 fibroblasts and that cells with defects to their antioxidant defense systems display endogenously increased levels of ETS-2 (46).…”

Inhibitory Effect of Electrolyzed Reduced Water on Tumor Angiogenesis

“…Another transcription factor, ETS-1, is up-regulated by H 2 O 2 via HIF1a which is stabilized by H 2 O 2 . 63,64) The HIF-1a (120 kDa) is complexed with HIF-1b (94 kDa) subunit forming functional HIF-1 (hypoxia-inducible factor-1). HIF-1a is the rate limiting subunit which determines the activity of the HIF-1 complex.…”

Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47 phox Gene Expression in Response to Angiotensin II

“…27,28 The role of Ets-1 as a downstream transcriptional effector of ROS has recently been demonstrated in several different cell types.The expression of Ets-1 is induced in a variety of ovarian cancer cell lines by H 2 O 2 . 29 The induction of Ets-1 in these cells is linked to increased binding of the transcription factor Nrf2 to an antioxidant response element within the Ets-1 gene promoter. H 2 O 2 is a tumor-derived factor that can stimulate cellular growth at low concentrations.…”