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Title: Nuclear receptor co-regulator Kruppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus

Author
item PABONA, JOHN MARK - ACNC/UAMS
item VELARDE, MICHAEL - UNIV OF CA/SAN FRANCISCO
item ZENG, ZHAOYANG - ACNC/UAMS
item SIMMEN, FRANK - ACNC/UAMS
item SIMMEN, ROSALIA - ACNC/UAMS

Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/3/2008
Publication Date: 1/15/2009
Citation: Pabona, J.P., Velarde, M.C., Zeng, Z., Simmen, F.A., Simmen, R.C. 2009. Nuclear receptor co-regulator Kruppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus. Journal of Endocrinology. 200(1):63-73.

Interpretive Summary: Estrogen is a steroid hormone that regulates the growth of uterine tissues. Many other factors are present in the normal uterus and in this important function of estrogen. Here we show that a protein named Krüppel-like factor 9 (Klf9) plays a significant role in controlling estrogen action. Klf9 regulates the expression of another protein namely Repressor of Estrogen Receptor Activity (REA) in the uterus. Absence of this regulation results in abnormal uterus with the tendency to grow uncontrollably and may lead to endometrial cancer.

Technical Abstract: 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 find that in ovariectomized mice administered estradiol-17ß (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 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.