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J. Biol. Chem., Vol. 281, Issue 36, 26683-26692, September 8, 2006

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Estrogen-induced Proliferation of Uterine Epithelial Cells Is Independent of Estrogen Receptor Binding to Classical Estrogen Response Elements^*

Jeanne E. O'Brien, Theresa J. Peterson, Ming Han Tong, Eun-Jig Lee^¶, Liza E. Pfaff, Sylvia C. Hewitt^||, Kenneth S. Korach^||, Jeffrey Weiss, and J. Larry Jameson¹

From the Divisions of Reproductive Endocrinology and Infertility and Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, the ^¶Division of Endocrinology, Yonsei University College of Medicine, Seoul 120-749, Korea, and the ^||Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 22709

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 ER, a mutant ER (E207A/G208A) that selectively lacks ERE binding, or ER null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17-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 ER signaling. This proliferative response was confirmed by 5-bromo-2'-deoxyuridine incorporation. Microarray experiments identified cyclin-dependent kinase inhibitor 1A as a nonclassical pathwayresponsive gene, and transient expression experiments using the cyclin-dependent kinase inhibitor 1A promoter confirmed transcriptional responses to the ER (E207A/G208A) mutant. These results indicate that nonclassical ER 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 ER plays a critical physiologic role in the uterine response to estrogen.

Received for publication, February 16, 2006 , and in revised form, July 5, 2006.

^* This work was supported by National Institutes of Health Grant PO1 HD21921 (to J. L. J.) NIH Training Grant T32 HD07068 (to T. J. P.), and the Division of Intramural Research, NIEHS, National Institutes of Health (to K. S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center for Genetic Medicine, Lurie 7-220, 303 E. Superior St., Feinberg School of Medicine Northwestern University, Chicago, IL 60611. Tel.: 312-926-9436; Fax: 312-926-7260; E-mail: ljameson{at}northwestern.edu.

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