A Novel Link Between Oxidative Stress Proteins and Estrogen Receptor Alpha-Mediated Gene Expression

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Rao, Abhilasha

Contributors dc:contributor

• Katzenellenbogen, Benita S.
• Nardulli, Ann M.

• Biology, Molecular
• Biology, Physiology

Identifier

(UMI)AAI3392443

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/72488