A Novel Link Between Oxidative Stress Proteins and Estrogen Receptor Alpha-Mediated Gene Expression
Rao, Abhilasha
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Permalink
https://hdl.handle.net/2142/72488
Description
Title
A Novel Link Between Oxidative Stress Proteins and Estrogen Receptor Alpha-Mediated Gene Expression
Author(s)
Rao, Abhilasha
Issue Date
2009
Doctoral Committee Chair(s)
Katzenellenbogen, Benita S.
Nardulli, Ann M.
Department of Study
Cell and Developmental Biology
Discipline
Cell and Developmental Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Biology, Physiology
Abstract
The classical genomic pathway for 17beta-estradiol (E 2) action involves binding to estrogen receptor alpha (ERalpha) in target cells, interaction with estrogen response element (ERE)-containing DNA, recruitment of coregulatory proteins, and modification of estrogen responsive genes. Because DNA-induced conformational changes in ERalpha structure alter complex formation, we were interested in identifying proteins associated with the ERE-bound receptor. Using a novel electrophoretic fractionation method, we identified a number of proteins involved in oxidative stress response including Cu/Zn superoxide dismutase (SOD1), thioredoxin (Trx) and thioredoxin reductase (TrxR). We found that SOD1 interacts with ERalpha, enhances ERalpha-ERE complex formation, influences estrogen responsiveness and associates with estrogen responsive regions of the pS2 and progesterone receptor genes. Furthermore, when MCF-7 breast cancer cells are exposed to E2 and superoxide SOD1 levels increase and oxidative stress-induced protein damage is greatly reduced. We also demonstrate that endogenously-expressed ERalpha, Trx, and TrxR interact, differentially influence endogenous estrogen-responsive gene expression, and alter hydrogen peroxide levels in MCF-7 cells. Additional characterization using brain slice cultures suggests a protective role for E2 and SOD1 in the cerebral cortex. These combined studies highlight a novel link between oxidative stress proteins and ERalpha-mediated gene expression in target tissues.
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