The long-range goal is to demonstrate the pathologic roles of novel progesterone-regulated genes in uterine leiomyoma tissue. We found that progesterone-bound progesterone receptor (PR) is recruited to multiple sites genome-wide and acts as a master-regulator of many genes in leiomyoma smooth muscle cells. In vivo, progesterone and its agonists cause growth of uterine leiomyomata, whereas treatment of patients with RU486 or other antagonists reduces the tumor size and decreases associated uterine bleeding. The mechanisms responsible for these actions of progesterone and its antagonists in uterine leiomyoma are not known. We hypothesize that progesterone regulates a number of critical genes that favors increased proliferation and decreased apoptosis of leiomyoma smooth muscle cells, whereas progesterone antagonists reverse these effects. Using two unbiased approaches, chromatin immunoprecipitation-PCR cloning and mRNA profiling by microarray, we identified two key genes, BCL2 and kruppel-like factor-11 (KLF11), which are highly regulated by progesterone and RU486 in vitro and in vivo. Progesterone-induced BCL2 expression led to an inhibition of leiomyoma cell apoptosis, whereas KLF11, a tumor-suppressor transcription factor and a novel target of PR, was downregulated by progesterone resulting in enhanced proliferation. RU486 inhibited BCL2 and induced KLF11 expression. To further define the roles of BCL2 and KLF11 as critical PR targets in uterine leiomyoma, we propose the following aims.
Aim 1 is to determine the mechanisms responsible for regulation of apoptosis via PR and BCL2 in leiomyoma smooth muscle cells and tissues. We hypothesize that progesterone and its antagonists regulate BCL2-mediated mitochondrial pathway of apoptosis via PR.
Aim 2 is to define the role of the novel PR-target gene KLF11 in regulating proliferation of uterine leiomyoma smooth muscle cells and tissues. We hypothesize that, via PR, progesterone enhances leiomyoma cell proliferation by inhibiting KLF11 expression, whereas its antagonists favor KLF11 expression and inhibit proliferation.
Aim 3 is to define PR-associated enhancer and inhibitory transcriptional complexes that occupy regulatory regions of BCL2 and KLF11 genes as a function of treatment of leiomyoma cells with progesterone or its antagonist. We will test the hypothesis that the promoter contexts of BCL2 and KLF11 determine differential recruitment of coregulators in response to treatment with progesterone or its antagonist resulting in transcriptional activation or repression.
Uterine leiomyomata represent the most prevalent benign gynecologic disorder. However, the underlying molecular and cellular mechanisms of leiomyoma growth and development are not well understood. We propose here in-depth molecular and cellular analysis of hormonal responsiveness of leiomyoma. Defining novel molecular targets of progestins and its antagonists will lead to development of more effective progesterone receptor modulators with fewer side effects for treating uterine leiomyoma.
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|Sefton, Elizabeth C; Qiang, Wenan; Serna, Vanida et al. (2013) MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth. Endocrinology 154:4046-57|
|Varghese, Binny V; Koohestani, Faezeh; McWilliams, Michelle et al. (2013) Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway. Proc Natl Acad Sci U S A 110:2187-92|
|Ono, Masanori; Yin, Ping; Navarro, Antonia et al. (2013) Paracrine activation of WNT/*-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A 110:17053-8|
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