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Differential Cell-Specific Modulation of HOXA10 by Estrogen and Specificity Protein 1 Response Elements

Departments of Obstetrics, Gynecology and Reproductive Sciences (R.M., M.B.T., G.K., C.L., G.E.A., H.S.T.) and Molecular, Cellular and Developmental Biology (H.S.T.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Hugh S. Taylor, Associate Professor, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208063, New Haven, Connecticut 06520-8063. E-mail: hugh.taylor{at}yale.edu.

Context: HOX genes are highly evolutionarily conserved regulators of embryonic development. HOXA10 also regulates differentiation of the adult reproductive tract and mammary gland in response to sex steroids.

Objective: We recently identified two HOXA10 estrogen response elements (EREs). Here we demonstrate that estrogen-responsive HOXA10 expression is cell type specific.

Design and Setting: We conducted an in vitro study at an academic medical center.

Main Outcome Measure: Reporter assay, gel shift assays (electrophoretic mobility shift assay), and immunohistochemistry were done.

Results: The HOXA10 EREs and a specificity protein 1 (Sp1) binding site differentially drive the cell-type-specific E2 response. In electrophoretic mobility shift assays, both estrogen receptor- and -ß bound both EREs but not the Sp1 site. In reporter assays, both EREs and the Sp1 site demonstrated estrogen responsiveness and tissue specificity; transiently transfected uterine Ishikawa cells or breast MCF-7 cells showed differential responses to E2 treatment. Each response element (Sp1, ERE1, and ERE2) drove distinct differential expression in each cell type. Sp1 protein was expressed in a menstrual-cycle stage-specific expression pattern in endometrium, first expressed in perivascular cells.

Conclusions: Tissue specificity inherent to a regulatory element as well as differential cellular expression of transcription factors imparts differential tissue-specific estrogen responsiveness.

This article has been cited by other articles:

				D. Vitiello, R. Pinard, and H. S. Taylor Gene Expression Profiling Reveals Putative HOXA10 Downstream Targets in the Periimplantation Mouse Uterus Reproductive Sciences, May 1, 2008; 15(5): 529 - 535. [Abstract] [PDF]