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This Article Full Text Full Text (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 M P Articles by Simmen, R C M Search for Related Content PubMed PubMed Citation Articles by Pabona, J M P Articles by Simmen, R C M

J M P Pabona^*, M C Velarde^*,, Z Zeng, F A Simmen

Department of Physiology and Biophysics, University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, 1212 Marshall Street, Little Rock, Arkansas 72202, USA

(Correspondence should be addressed to R C M Simmen; Email: simmenrosalia{at}uams.edu)

^* (J M P Pabona and M C Velarde contributed equally to this study and are considered as co-first authors)

M C Velarde is now at Department of OB/GYN and Reproductive Sciences, University of California San Francisco, San Francisco, California 94143, USA

Estrogen, acting through its cognate receptor estrogen receptor- (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) 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 Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found 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 demonstrated a negative association between Klf9 expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E₂-treated wild-type (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 ST and epithelial cells, with no effects on the expression of the related Phb1. In the human endometrial ST cell line 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 estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.