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-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 ER alpha and the proapoptotic forkhead transcription factor FKHR. The ER alpha-FKHR interaction depends on beta-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 ER alpha and was not detected with other ligand-activated steroid receptors. The related family members, FKHRL1 and AFX, also bound to ER alpha in the presence of beta-estradiol. FKHR augmented ER alpha transactivation through an estrogen response element. Conversely, ER alpha 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.
Schuur
E R
ER
Department of Surgery and Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.
Loktev
A V
AV
Sharma
M
M
Sun
Z
Z
Roth
R A
RA
Weigel
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004958:Estradiol / Q000737:chemistry; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology; D051858:Forkhead Transcription Factors; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry*; D012097:Repressor Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051858:Forkhead Transcription Factors; D008024:Ligands; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014157:Transcription Factors; D013629:Tamoxifen; D004958:Estradiol; D004247:DNA; D005982:Glutathione Transferase