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Foxl2, a Forkhead Transcription Factor, Modulates Nonclassical Activity of the Estrogen Receptor-

Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Morton 4-656, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: ljameson{at}northwestern.edu.

Foxl2 is a forkhead transcription factor required for ovary development and ovarian follicle maturation. In this report, we identified and characterized a functional relationship between Foxl2 expression and estrogen receptor (ER)- signaling. We show that Foxl2 has no effect on classical ER-mediated transcription, which occurs through canonical estrogen response elements. However, Foxl2 suppresses ER signaling through nonclassical tethered transcriptional pathways. Specifically, the selective ER modulator tamoxifen stimulates activator protein-1 (AP1)-dependent transcription via the ER, and this enhancement is blocked by Foxl2. Two lines of evidence suggest that Foxl2 suppression is mediated by physical interactions with ER rather than direct action at AP1 binding sites. First, ER is coimmunoprecipitated with Foxl2. Second, activation of a upstream activating sequence (UAS) reporter by Gal4-cJun in the presence of ER and tamoxifen was blocked by Foxl2, demonstrating suppression in the absence of an AP1 site. Cyclooxygenase-2 (COX2), which is required for ovulation, was identified through expression profiling as a candidate physiological target for nonclassical ER signaling and thus modulation by ER/Foxl2 interactions. This possibility was confirmed by two sets of experiments. COX2 protein levels were induced by ER in the presence of tamoxifen, and protein expression was suppressed by Foxl2. In addition, ER stimulation of the COX2 promoter was repressed by Foxl2. We conclude that ER and Foxl2 interact and that Foxl2 selectively suppresses ER-mediated transcription of AP1-regulated genes. These data provide a potential point of convergence for ER and Foxl2 to regulate ovarian development and function.