Protein disulfide isomerase is a multifunctional regulator of estrogenic status in target cells.
Earlier studies showed that protein disulfide isomerase (PDI), a well-known protein folding catalyst and a molecular chaperone, can bind estrogens and may also directly interact with the estrogen receptor (ER). In this study, we sought to determine the biological functions of these intriguing properties of PDI. We showed that PDI can function as a high-capacity intracellular 17beta-estradiol (E(2))-binding protein that increases the concentration and accumulation of E(2) in live cells. The intracellular PDI-bound E(2) can be released from PDI upon a drop in E(2) levels and the released E(2) can augment estrogen receptor-mediated transcriptional activity and mitogenic actions in cultured cells. In addition, the binding of E(2) by PDI also reduces the rate of metabolic disposition of this hormone. We showed, for the first time, that knockdown of PDI in MCF-7 human breast cancer cells with RNA interference down-regulates ERalpha protein but up-regulates ERbeta protein, resulting in a drastic increase in ERbeta/ERalpha ratio, which is a crucial determinant of different cellular responses to estrogens. To explain the mechanism of this differential regulation, we also studied the interactions of PDI with ERalpha and ERbeta. We found that PDI can directly interact with ERalpha, but it does not interact with ERbeta. Altogether, these data showed that PDI is a multifunctional regulator of intracellular estrogenic status. It not only regulates the intracellular concentrations of E(2) and the magnitude of estrogen action, but it also modulates the ERbeta/ERalpha ratio.
Fu
Xinmiao
X
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Wang
Pan
P
Zhu
Bao Ting
BT
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011994:Recombinant Proteins; D004958:Estradiol; D019704:Protein Disulfide-Isomerases