title: Protein disulfide isomerase serves as a molecular chaperone to maintain estrogen receptor alpha structure and function.
abstract: The effects of the steroid hormone 17beta-estradiol are mediated through its interaction with the nuclear estrogen receptor (ER). Upon binding 17beta-estradiol, the ER initiates changes in gene expression through its interaction with specific DNA sequences, estrogen response elements (EREs), and recruits coregulatory proteins that influence gene expression. To better understand how estrogen-responsive genes are regulated, we have isolated and identified proteins associated with ERalpha when it is bound to the consensus ERE. One of these proteins, protein disulfide isomerase (PDI), has two distinct functions: acting as a molecular chaperone to maintain properly folded proteins and regulating the redox state of proteins by catalyzing the thiol-disulfide exchange reaction through two thioredoxin-like domains. Using a battery of biochemical and molecular techniques, we have demonstrated that PDI colocalizes with ERalpha in MCF-7 nuclei, alters ERalpha conformation, enhances the ERalpha-ERE interaction in the absence and presence of an oxidizing agent, influences the ability of ERalpha to mediate changes in gene expression, and associates with promoter regions of two endogenous estrogen-responsive genes. Our studies suggest that PDI plays a critical role in estrogen responsiveness by functioning as a molecular chaperone and assisting the receptor in differentially regulating target gene expression.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Schultz-Norton
authors.forename: W Hayes
authors.initials: WH
authors.lastname: McDonald
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Ann M
authors.initials: AM
authors.lastname: Nardulli
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D018832:Molecular Chaperones; D004247:DNA; D019704:Protein Disulfide-Isomerases