Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family

• Published in: The Journal of biological chemistry 2001-09, Vol.276 (36), p.33554-33560
• Main Authors: Schuur, Eric R., Loktev, Alexander V., Sharma, Manju, Sun, Zijie, Roth, Richard A., Weigel, Ronald J.
• Format: Article
• Language: English
• Subjects: AFX protein; Amino Acid Sequence; Animals; Apoptosis; b-estradiol; Binding Sites; Cell Cycle; Cell Nucleus - metabolism; COS Cells; DNA - metabolism; DNA, Complementary - metabolism; Estradiol - chemistry; Estrogen Receptor alpha; Estrogens - pharmacology; FKHR protein; FKHRL1 protein; Forkhead Transcription Factors; Genes, Reporter; Glutathione Transferase - metabolism; Humans; Ligands; Molecular Sequence Data; Nuclear Proteins - chemistry; Plasmids - metabolism; Protein Binding; Protein Structure, Tertiary; Receptors, Estrogen - chemistry; Repressor Proteins - metabolism; Tamoxifen - pharmacology; Transcription Factors - chemistry; Transcriptional Activation; Tumor Cells, Cultured; Two-Hybrid System Techniques
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M105555200

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.