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This Article Accepted manuscript (PDF) All Versions of this Article: JME-09-0053v1 43/6/251    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Rao, A. Articles by Nardulli, A. PubMed PubMed Citation Articles by Rao, A. Articles by Nardulli, A.

A Rao, Cell and Developmental Biology, UIUC, Urbana, United States
Y Ziegler, Molecular & Integrative Physiology, UIUC, Urbana, United States
I McLeod, Department of Cell Biology, The Scripps Institute, LaJolla, United States
J Yates, Cell Biology, The Scripps Institute, LaJolla, United States
A Nardulli, Molecular & Integrative Physiology, University of Illinois, Urbana, 61801, United States

Correspondence: Ann Nardulli, Email: anardull{at}life.uiuc.edu

Abstract

Accumulation of reactive oxygen species (ROS) in cells damages resident proteins, lipids, and DNA. In order to overcome the oxidative stress that occurs with ROS accumulation, cells must balance free radical production with an increase in the level of antioxidant enzymes that convert free radicals to less harmful species. We identified two antioxidant enzymes, thioredoxin (Trx) and thioredoxin reductase (TrxR) in a complex associated with the DNA-bound estrogen receptor alpha (ER). Western analysis and immunocytochemistry were used to demonstrate that Trx and TrxR are expressed in the cytoplasm and in the nuclei of MCF-7 human breast cancer cells. More importantly, endogenously-expressed ER, Trx, and TrxR interact and ER and TrxR associate with the native, estrogen-responsive pS2 and PR genes in MCF-7 cells. RNA interference assays demonstrated that Trx and TrxR differentially influence estrogen-responsive gene expression and that together, 17β-estradiol (E2), Trx, and TrxR alter hydrogen peroxide (H2O2) levels in MCF-7 cells. Our findings suggest that Trx and TrxR are multifunctional proteins that, in addition to modulating H2O2 levels and transcription factor activity, aid ER in regulating expression of estrogen-responsive genes in target cells.