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SP1 and SP3 Mediate Progesterone-Dependent Induction of the 17beta Hydroxysteroid Dehydrogenase Type 2 Gene in Human Endometrium¹

Division of Reproductive Biology Research,³ Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3095 Department of Pathology,⁴ Tohoku University School of Medicine, Sendai 980-8575, Japan

ABSTRACT

The opposing actions of estrogen and progesterone during the menstrual cycle regulate the cyclical and predictable endometrial proliferation and differentiation that is required for implantation. Progesterone indirectly stimulates the expression of 17beta hydroxysteroid dehydrogenase type 2(HSD17B2), which catalyzes the conversion of biologically potent estradiol to weakly estrogenic estrone in the endometrial epithelium. We previously demonstrated upregulation of theHSD17B2gene in human endometrial epithelial cells by factors secreted from endometrial stromal cells in response to progesterone. We investigated the underlying mechanism by which these stroma-derived, progesterone-induced paracrine factors stimulateHSD17B2expression. Here, we show that transcription factors SP1and SP3 interact with specific motifs inHSD17B2promoter to upregulate enzyme expression in human endometrial epithelial cell lines. Conditioned medium (CM) from progestin-treated stromal cells increased levels of SP1 and SP3 in endometrial epithelial cells and inducedHSD17B2mRNA expression. Mithramycin A, an inhibitor of SP1-DNA interaction, reduced epithelialHSD17B2promoter activity in a dose-dependent manner. Serial deletion and site-directed mutants of theHSD17B2promoter demonstrated that two overlapping SP1 motifs (nt –82/–65) are essential for induction of promoter activity by CM or overexpression of SP1/SP3. CM markedly enhanced, whereas anti-SP1/SP3 antibodies inhibited, binding of nuclear proteins to this region of theHSD17B2promoter. In vivo, we demonstrated a significant spatiotemporal association between epithelial SP1/SP3 and HSD17B2levels in human endometrial biopsies. Taken together, these data suggest thatHSD17B2expression in endometrial epithelial cells, and, therefore, estrogen inactivation, is regulated by SP1 and SP3, which are downstream targets of progesterone-dependent paracrine signals originating from endometrial stromal cells.

endometrium, estradiol, estradiol receptor, estrogen metabolism, HSD17B2, menstrual cycle, paracrine regulation, progesterone receptor, SP1, SP3, uterus

¹ Supported by National Institutes of Health grant HD40093 to S.E.B. and grants from the Friends of Prentice and AVON Foundation.

² Correspondence: Serdar E. Bulun, Northwestern University, Feinberg School of Medicine, Robert H. Lurie Medical Research Center, 303 E. Superior Street, Suite 4–123, Chicago, IL 60611-3095. FAX: 312 503 0095; s-bulun{at}northwestern.edu

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				Y.-H. Cheng, P. Yin, Q. Xue, B. Yilmaz, M. I. Dawson, and S. E. Bulun Retinoic Acid (RA) Regulates 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometrium: Interaction of RA Receptors with Specificity Protein (SP) 1/SP3 for Estradiol Metabolism J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1915 - 1923. [Abstract] [Full Text] [PDF]

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