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

Jeanne E. O'Brien, Theresa J. Peterson, Han Tong Ming, Eun Jig Lee, Liza E. Pfaff, Sylvia C. Hewitt, Kenneth S. Korach, Jeffrey Weiss, J. Larry Jameson

Research output: Contribution to journalArticle

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Abstract

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 ERα, a mutant ERα (E207A/G208A) that selectively lacks ERE binding, or ERα null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17β-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 ERα 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 ERα (E207A/G208A) mutant. These results indicate that nonclassical ERα 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 ERα plays a critical physiologic role in the uterine response to estrogen.

Original languageEnglish
Pages (from-to)26683-26692
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number36
DOIs
Publication statusPublished - 2006 Sep 8

Fingerprint

Response Elements
Estrogen Receptors
Estrogens
Epithelial Cells
Cyclin-Dependent Kinases
Gene Expression
Gene expression
Estradiol
Transcription Factor AP-1
Hyperemia
Bromodeoxyuridine
Microarrays
Heterozygote
Uterus
Proteins
Transcription Factors
Genes
Experiments
Alleles
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

O'Brien, Jeanne E. ; Peterson, Theresa J. ; Ming, Han Tong ; Lee, Eun Jig ; Pfaff, Liza E. ; Hewitt, Sylvia C. ; Korach, Kenneth S. ; Weiss, Jeffrey ; Jameson, J. Larry. / Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor α binding to classical estrogen response elements. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 36. pp. 26683-26692.
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abstract = "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 ERα, a mutant ERα (E207A/G208A) that selectively lacks ERE binding, or ERα null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17β-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 ERα 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 ERα (E207A/G208A) mutant. These results indicate that nonclassical ERα 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 ERα plays a critical physiologic role in the uterine response to estrogen.",
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Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor α binding to classical estrogen response elements. / O'Brien, Jeanne E.; Peterson, Theresa J.; Ming, Han Tong; Lee, Eun Jig; Pfaff, Liza E.; Hewitt, Sylvia C.; Korach, Kenneth S.; Weiss, Jeffrey; Jameson, J. Larry.

In: Journal of Biological Chemistry, Vol. 281, No. 36, 08.09.2006, p. 26683-26692.

Research output: Contribution to journalArticle

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AU - O'Brien, Jeanne E.

AU - Peterson, Theresa J.

AU - Ming, Han Tong

AU - Lee, Eun Jig

AU - Pfaff, Liza E.

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AU - Korach, Kenneth S.

AU - Weiss, Jeffrey

AU - Jameson, J. Larry

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AB - 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 ERα, a mutant ERα (E207A/G208A) that selectively lacks ERE binding, or ERα null. In the compound heterozygote (AA/-) female, the nonclassical allele (AA) was insufficient to mediate an acute uterotrophic response to 17β-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 ERα 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 ERα (E207A/G208A) mutant. These results indicate that nonclassical ERα 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 ERα plays a critical physiologic role in the uterine response to estrogen.

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