Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family

Estrogen acting through the estrogen receptor (ER) is able to regulate cell growth and differentiation of a variety of normal tissues and hormone-resp onsive tumors. Ligand-activated DR binds DNA and transactivates the promote rs of estrogen target genes. In addition, ligand-activated ER can interact with other factors to alter the physiology and growth of cells. Using a yea st two-hybrid screen, we have identified an interaction between ER alpha an d the proapoptotic forkhead transcription factor FKHR. The ER alpha -FKHR i nteraction depends on beta -estradiol and is reduced significantly in the a bsence of hormone or the presence of Tamoxifen. A glutathione S-transferase pull-down assay was used to confirm the interaction and localized two inte raction sites, one in the forkhead domain and a second in the carboxyl term inus. The FKHR interaction was specific to ER alpha and was not detected wi th other ligand-activated steroid receptors. The related family members, FK HRL1 and AFX, also bound to ER alpha in the presence of beta -estradiol. FK HR augmented ER alpha transactivation through an estrogen response element. Conversely, ER alpha repressed FKHR-mediated transactivation through an in sulin response sequence, and cell cycle arrest induced by FKHRL1 in MCF7 ce lls was abrogated by estradiol. These results suggest a novel mechanism of estrogen action that involves regulation of the proapoptotic forkhead trans cription factors.