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Estrogen-induced Proliferation of Uterine Epithelial Cells Is Independent of Estrogen Receptor α Binding to Classical Estrogen Response Elements
Ist Teil von
The Journal of biological chemistry, 2006-09, Vol.281 (36), p.26683
Ort / Verlag
American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2006
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 (E 2 ). The uterine epithelial proliferative response to E 2 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-2â²-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 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.
Sprache
Englisch
Identifikatoren
ISSN: 0021-9258
eISSN: 1083-351X
DOI: 10.1074/jbc.M601522200
Titel-ID: cdi_highwire_biochem_281_36_26683
Format
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