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Endocrinology Vol. 140, No. 5 2268-2279
Copyright © 1999 by The Endocrine Society

ARTICLES

Identification of a GABP{alpha}/ß Binding Site Involved in the Induction of Oxytocin Receptor Gene Expression in Human Breast Cells. Potentiation by c-Fos/c-Jun1

Sarasija Hoare, John A. Copland, Thomas G. Wood, Yow-Jiun Jeng, Michael G. Izban and Melvyn S. Soloff

Department of Obstetrics and Gynecology (S.H., J.A.C., Y.-J.J., M.G.I., M.S.S.), and the Sealy Center for Molecular Science (T.G.W., M.G.I., M.S.S.), University of Texas Medical Branch, Galveston, Texas 77555-1062

Address all correspondence and requests for reprints to: Dr. Melvyn S. Soloff, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1062. E-mail: msoloff{at}utmb.edu

Oxytocin (OT) receptors (OTRs) mediate reproductive functions, including the initiation of labor and milk ejection. OTR messenger RNA levels are highly regulated, reaching the greatest concentration in the uterus at the end of gestation, and in the mammary gland during lactation. Factors directly effecting changes in OTR gene expression in the mammary gland are not known, so the present studies were done to elucidate possible regulators by characterizing the human OTR gene promoter and 5'-flanking sequence. By analyzing expression of promoter-luciferase constructs, we localized a region between -85 and -65 that was required for both basal and serum-induced expression in a mammary tumor cell line (Hs578T) that expresses inducible, endogenous OTRs. This DNA region contains an ets family target sequence (5'-GGA-3'), and a CRE/AP-1-like motif. The specific Ets factor binding to the OTR promoter was identified, by electrophoretic mobility immunoshift assays, to be GABP{alpha}/ß. Cotransfection of a -85 OTR/luciferase construct with vectors expressing GABP{alpha} and GABPß1 had only a modest effect on expression, but cotransfection with GABP{alpha}/ß- with c-Fos/c-Jun-expressing plasmids resulted in an increase of almost 10-fold in luciferase activity. Mutation of either the GABP- or CRE-like binding sites obliterated the induction. These findings are consistent with the involvement of protein kinase C activity in serum induction of the endogenous gene in Hs578T cells. We showed the requirement for GABP{alpha}/ß and c-Fos/c-Jun in endogenous OTR gene expression, using oligonucleotide GABP and AP-1 binding decoys to inhibit serum-induced increases in 125I-labeled OT antagonist binding to Hs578T cells. Our work is the first characterization of the proximal promoter region of the human OTR gene, and it sets the stage for studying regulation of OTR expression in breast cells.




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