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Cooperative Control via Lymphoid Enhancer Factor 1/T Cell Factor 3 and Estrogen Receptor- for Uterine Gene Regulation by Estrogen

Division of Reproductive and Developmental Biology, Departments of Pediatrics (S.R., F.X., H.W., S.K.D.) and Cancer Biology (S.R., F.X., S.K.D.), Vanderbilt University Medical Center, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Sanjoy K. Das, Ph.D., Division of Reproductive and Developmental Biology, Department of Pediatrics, D-4105 Medical Center North, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232-2678. E-mail: sanjoy.das{at}vanderbilt.edu.

Accumulating evidence indicates that estrogen regulates diverse but interdependent signaling pathways via estrogen receptor (ER)-dependent and -independent mechanisms. However, molecular relationship between these pathways for gene regulation under the direction of estrogen remains unknown. To address this possibility, our uterine analysis of Wnt/β-catenin downstream effectors revealed that lymphoid enhancer factor 1 (Lef-1) and T cell factor 3 (Tcf-3) are up-regulated temporally by 17β-estradiol (E₂) in an ER-independent manner. Lef-1 is abundantly up-regulated early (within 2 h), whereas Tcf-3 is predominantly induced after 6 h, and both are sustained through 24 h. Interestingly, activated Lef-1/Tcf-3 molecularly interacted with ER in a time-dependent manner, suggesting they possess a cross talk in the uterus by E₂. Moreover, dual immunofluorescence studies confirm their colocalization in uterine epithelial cells after E₂. Most importantly, using chromatin immunoprecipitation followed by PCR analyses, we provide evidence for an interesting possibility that ER and Tcf-3/Lef-1 complex occupies at certain DNA regions of estrogen-responsive endogenous gene promoters in the mouse uterus. By selective perturbation of activated Lef-1/Tcf-3 or ER signaling events, we provide in this study novel evidence that cooperative interactions, by these two different classes of transcription factors at the level of chromatin, direct uterine regulation of estrogen-responsive genes. Collectively, these studies support a mechanism that integration of a nonclassically induced β-catenin/Lef-1/Tcf-3 signaling with ER is necessary for estrogen-dependent endogenous gene regulation in uterine biology.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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