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Title: Redox Regulation of Estrogen Receptor alpha and Sodium Hydrogen Exchanger 1 Gene Expression by Hydrogen Peroxide
Keywords: ER, NHE1, redox, gene regulation, hydrogen peroxide, gene expression
Issue Date: 16-Mar-2011
Citation: CHUA SUI HUAY (2011-03-16). Redox Regulation of Estrogen Receptor alpha and Sodium Hydrogen Exchanger 1 Gene Expression by Hydrogen Peroxide. ScholarBank@NUS Repository.
Abstract: There is mounting evidence that implicates reactive oxygen species (ROS) as an important signaling molecule in various physiological processes. In contrast to the wealth of information on gene up-regulation by ROS, little attention has been paid to the down-regulation of gene expression by ROS. In this thesis, we have studied how two important genes, estrogen receptor alpha (ERa) and sodium hydrogen exchanger 1 (NHE1) were redox-regulated by H2O2. In the first part of the study, the regulation of ERa by oxidative stress induced by the exposure of MCF7 cells to H2O2 was investigated. The data supported that ERa protein is down-regulated when exposed to oxidative stress. The down-regulation of ERa protein occurs not through proteosomal degradation pathway, but via the decrease in ERa mRNA level. We found that Akt, MAPK and caspases were not involved in the down-regulation of ERa by H2O2. Instead, H2O2 inhibition of ERa expression involves an oxidation event that is reversible by the addition of reducing agent, DTT. We also demonstrated that 15d-PGJ2 suppressed ERa expression via the production of ROS. ERa down-regulation resulted in decreased ERa-responsive gene expression and impaired estrogen signaling. These effects could have contributed to the growth arrest observed in H2O2 treated MCF7 cells. In the second part of the study, the down-regulation of NHE1 by H2O2 was examined. We found that the minimal promoter region required for full transcription activation lies on the 0.15kb of NHE1 promoter. This region is also regulated by H2O2. The regulation of NHE1 by H2O2 is similar to the regulation of ERa. H2O2 targets NHE1 at the mRNA level in a reversible manner. The down-regulation involves an oxidation mechanism which is reversible by reducing agents DTT and BME. The drug 15d-PGJ2 was also shown to down-regulate NHE1 promoter activity via the production of ROS. Finally, the data suggested that AP2 is not the transcription factor for NHE1 and is not a target in H2O2 mediated down-regulation of NHE1.
Appears in Collections:Ph.D Theses (Open)

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