Journal of Biological Chemistry
Volume 276, Issue 36, 7 September 2001, Pages 33554-33560
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GENES: STRUCTURE AND REGULATION
Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family*

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Estrogen acting through the estrogen receptor (ER) is able to regulate cell growth and differentiation of a variety of normal tissues and hormone-responsive tumors. Ligand-activated ER binds DNA and transactivates the promoters of estrogen target genes. In addition, ligand-activated ER can interact with other factors to alter the physiology and growth of cells. Using a yeast two-hybrid screen, we have identified an interaction between ERα and the proapoptotic forkhead transcription factor FKHR. The ERα-FKHR interaction depends on β-estradiol and is reduced significantly in the absence of hormone or the presence of Tamoxifen. A glutathione S-transferase pull-down assay was used to confirm the interaction and localized two interaction sites, one in the forkhead domain and a second in the carboxyl terminus. The FKHR interaction was specific to ERα and was not detected with other ligand-activated steroid receptors. The related family members, FKHRL1 and AFX, also bound to ERα in the presence of β-estradiol. FKHR augmented ERα transactivation through an estrogen response element. Conversely, ERα repressed FKHR-mediated transactivation through an insulin response sequence, and cell cycle arrest induced by FKHRL1 in MCF7 cells was abrogated by estradiol. These results suggest a novel mechanism of estrogen action that involves regulation of the proapoptotic forkhead transcription factors.

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Published, JBC Papers in Press, July 2, 2001, DOI 10.1074/jbc.M105555200

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This work was supported in part by National Institutes of Health Grant R01 CA77350.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.