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DNA-Binding Ability of NF-B is Affected Differently by ER and ERβ and Its Activation Results in Inhibition of Estrogen Responsiveness

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Gulden Halis, MD

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, Endometriosezentrum Berlin, Department of Obstetrics and Gynecology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany

Sarper Taskiran, MD

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Umit A. Kayisli, PhD

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Aydin Arici, MD

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, aydin.arici{at}yale.edu

Estrogenic effects involve interactions between estrogen receptors (ERs), response elements, and nuclear proteins. It is hypothesized that interaction between ER and NF- B may affect the regulation of responsive genes. Electrophoretic mobility shift assay (EMSA) was performed to assess if the interaction of ERs and NF- B affect their respective DNA-binding activities, and alkaline phosphatase assay was done to evaluate estrogenic activity. EMSA revealed that ERs inhibit DNA-binding of p50 and p65, whereas p50 did not impair ER binding. Stimulation with estradiol inhibited DNA binding of NF-B in ER-transfected endometrial stromal cells (ESCs). Moreover, activation of NF-B significantly decreased estrogen responsiveness of Ishikawa cells and ER-transfected ESC. Our results suggest that ERs downregulate NF-B-dependent gene activation by directly preventing DNA binding. However, NF-B-mediated inhibition of ER-dependent gene activation may be carried out indirectly rather than through a direct inhibition of ER-DNA binding. These findings offer new insight into the specific role of ER and could eventually help in developing therapeutics for endometriosis.

Key Words: Estrogen receptors and β • nuclear factor-B • EMSA • endometrium • estrogen • endometriosis.

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