Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor α binding to classical estrogen response elements

Division of Reproductive Endocrinology and Infertility, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2006; 281(36):26683-92. DOI: 10.1074/jbc.M601522200
Source: PubMed


Acting via the estrogen receptor (ER), estradiol exerts pleomorphic effects on the uterus, producing cyclical waves of cellular proliferation and differentiation in preparation for embryo implantation. In the classical pathway, the ER binds directly to an estrogen response element to activate or repress gene expression. However, emerging evidence supports the existence of nonclassical pathways in which the activated ER alters gene expression through protein-protein tethering with transcription factors such as c-Fos/c-Jun B (AP-1) and Sp1. In this report, we examined the relative roles of classical and nonclassical ER signaling in vivo by comparing the estrogen-dependent uterine response in mice that express wild-type ERalpha, a mutant ERalpha (E207A/G208A) that selectively lacks ERE binding, or ERalpha null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17beta-estradiol (E2). The uterine epithelial proliferative response to E2 and 4-hydroxytamoxifen was retained in the AA/-females, and uterine luminal epithelial height increased commensurate with the extent of ERalpha signaling. This proliferative response was confirmed by 5-bromo-2'-deoxyuridine incorporation. Microarray experiments identified cyclin-dependent kinase inhibitor 1A as a nonclassical pathway-responsive gene, and transient expression experiments using the cyclin-dependent kinase inhibitor 1A promoter confirmed transcriptional responses to the ERalpha (E207A/G208A) mutant. These results indicate that nonclassical ERalpha signaling is sufficient to restore luminal epithelial proliferation but not other estrogen-responsive events, such as fluid accumulation and hyperemia. We conclude that nonclassical pathway signaling via ERalpha plays a critical physiologic role in the uterine response to estrogen.

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Available from: Kenneth S Korach, Nov 23, 2015
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    • "One of the proliferative responses of the uterine epithelium is hyperplasia and stratification of the epithelial cells which affect the implantation phase. Therefore increasing the height of endometrial and fallopian epithelial cells can improve the proliferative indices (12,13). Previously it has been demonstrated that exposure to extremely low-frequency electromagnetic field (ELF-EMF) can increase height of fallopian tube epithelial cells. "
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    • "Although ERα is a nuclear receptor mediating most of its pleiotrophic effects as a DNA-binding transcription factor, several reports have suggested that estrogen receptors are also capable of associating with the cell membrane to conduct rapid responses independent of gene expression [11], [12]. Alternatively ERα was reported to suppress gene transcription by interfering with DNA-bound transcription factors such as AP-1 [13]. In this regard it is important to state that we have previously reported that glucocorticoid-induced bone loss still occurs in mice carrying a glucocorticoid receptor incapable of DNA-binding [14]. "
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