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Title: Nuclear Receptor Coregulators Krüppel-like Factor 9 and Prohibitin 2 Expression in Estrogen-Stimulated Proliferation of Mouse Uterine Endometrial Cells

Author
item PABONA, JOHN - ACNC/UAMS
item ZENG, ZHAOYANG - ACNC/UAMS
item VELARDE, MICHAEL - ACNC/UAMS
item SIMMEN, FRANK - ACNC/UAMS
item SIMMEN, ROSALIA - ACNC/UAMS

Submitted to: Journal of Endocrinology
Publication Type: Abstract Only
Publication Acceptance Date: 3/15/2008
Publication Date: 6/15/2008
Citation: Pabona, J.M., Zeng, Z., Velarde, M., Simmen, F.A., Simmen, R.C. 2008. Nuclear receptor coregulators Krüppel-like Factor 9 and prohibitin 2 expression in estrogen-stimulated proliferation of mouse uterine endometrial cells [abstract]. The Endocrine Society, 90th Annual Meeting, June 15-18, 2008, San Francisco, California. 2008 CDROM, Program No. P3-37.

Interpretive Summary: Estrogen binds to estrogen receptor-alpha (ER alpha) protein, which influences many physiological processes by interacting with other nuclear receptor coactivator and corepressor regulatory proteins in target tissues. Sp1-related transcription factor Kruppel-like factor 9 (KLF9) was previously been identified for the uterine cell proliferation and function. Mice null to KLF9 were found to be subfertile. In this study, we showed that Klf9 positively regulates endometrial cell proliferation by decreasing the expression of prohibitin 2 (PHB2), also known as Repressor of estrogen Activity (REA), which binds to ER alpha and interferes interaction with other coactivators.

Technical Abstract: Estrogen receptor-alpha (ER alpha) influences many physiological processes by binding to its ligand estrogen (E2) and interacting with nuclear receptor coactivator and corepressor proteins to regulate transcription in target tissues. In the uterus, dysregulated ER-alpha activity leads to aberrant cellular proliferation, resulting in pregnancy failure and pathological conditions such as endometriosis and adenocarcinoma. We previously showed that Kruppel-like factor 9 (KLF9), an Sp1-related transcription factor, contributes to the control of uterine cell proliferation and function since a) KLF9 null mice were subfertile, due partly to reduced proliferation of glandular epithelial (GE), luminal epithelial (LE), and stromal (ST) cells in the E2-dominated uterus at early pregnancy; and b) overexpression of a full-length KLF9 construct in the human endometrial cell line HEC-1A resulted in increased proliferation relative to that expressing the antisense KLF9 construct. Herein, we tested the hypothesis that KLF9 positively regulates endometrial cell proliferation by inhibiting the expression of prohibitin 2 (PHB2), also known as Repressor of Estrogen receptor Activity (REA), which binds to ER alpha and interferes with the latter's ability to interact with co-activators. In the peri-implantation mouse uterus, PHB2/REA expression, measured by quantitative RT-PCR, was significantly higher in KLF9 null than in wildtype (WT) mice at day post-coitum (dpc) 2.5 and 4.5, but not at dpc 3.5. The increased expression of PHB2/REA with loss of KLF9 was accompanied by attenuated ER alpha gene expression. KLF9 had no effect on the expression of the closely related ERa corepressor prohibitin. E2 administration for 24 h decreased uterine PHB2/REA gene expression in ovariectomized WT relative to vehicle-treated counterparts; this was observed coincident with increased PCNA immunoreactivity in corresponding LE, GE, and ST cells. In ovariectomized KLF9 null mice, E2 treatment for 24 h increased uterine PHB2/REA gene expression, concomitant with the loss of proliferative responsiveness of all cell types, relative to ovariectomized WT mice. There was no association between PHB2/REA and ER alpha, and between prohibitin and KLF9 mRNA levels under this context. Results indicate that KLF9 may negatively regulate PHB2/REA expression in an E2-dominated environment and suggest that cellular levels of KLF9 may constitute an important determinant in ligand-dependent ER-alpha regulation of uterine cell proliferation.