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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0383v1 200/1/63    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pabona, J. Articles by Simmen, R. Search for Related Content PubMed PubMed Citation Articles by Pabona, J. Articles by Simmen, R.

J Pabona, Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States
M Velarde, Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States
Z Zeng, Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States
F Simmen, Little Rock, United States
R Simmen, Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, 72202, United States

Correspondence: Rosalia Simmen, Email: SimmenRosalia{at}uams.edu

Abstract

Oestrogen, acting through its cognate receptor oestrogen receptor- (ER), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in stromal-epithelial interactions underlying proliferative effects of oestrogen. We find that in ovariectomized mice administered estradiol-17β(E2) for 24 h, Klf9 null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrate a negative association between Klf9 expression and nuclear levels of ER transcriptional corepressor prohibitin (PHB) 2 in uterine stromal and epithelial cells of E2-treated wildtype (WT) and Klf9 null mice. In early pregnancy uteri of WT mice, the temporal pattern of Klf9 transcript levels was inversely associated with that of Phb2. Deletion of Klf9 up-regulated uterine Phb2 expression and increased PHB2 nuclear localization in endometrial stromal and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial stromal cell line HESC treated with E2 for 24 h, KLF9 siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seen in vivo with Klf9 null mutants. Our findings suggest a novel mechanism for control of oestrogen-induced luminal epithelial proliferation involving stromal KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.