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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.

Pubmed ID: 11435445

Authors

  • Schuur ER
  • Loktev AV
  • Sharma M
  • Sun Z
  • Roth RA
  • Weigel RJ

Journal

The Journal of biological chemistry

Publication Data

September 7, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA070297
  • Agency: NCI NIH HHS, Id: R01 CA070297-06A1
  • Agency: NCI NIH HHS, Id: R01 CA070297-07
  • Agency: NCI NIH HHS, Id: R01 CA070297-08
  • Agency: NCI NIH HHS, Id: R01 CA070297-09
  • Agency: NCI NIH HHS, Id: R01 CA070297-10
  • Agency: NCI NIH HHS, Id: R01 CA070297-11A2
  • Agency: NCI NIH HHS, Id: R01 CA070297-12
  • Agency: NCI NIH HHS, Id: R01 CA087767
  • Agency: NCI NIH HHS, Id: R01 CA087767-01A2
  • Agency: NCI NIH HHS, Id: R01 CA087767-02
  • Agency: NCI NIH HHS, Id: R01 CA087767-03
  • Agency: NCI NIH HHS, Id: R01 CA087767-04
  • Agency: NCI NIH HHS, Id: R01 CA087767-05
  • Agency: NCI NIH HHS, Id: R01 CA77350
  • Agency: NIDDK NIH HHS, Id: R01 DK061002
  • Agency: NIDDK NIH HHS, Id: R01 DK061002-01A1
  • Agency: NIDDK NIH HHS, Id: R01 DK061002-02
  • Agency: NIDDK NIH HHS, Id: R01 DK061002-03
  • Agency: NIDDK NIH HHS, Id: R01 DK061002-04
  • Agency: NIDDK NIH HHS, Id: R01 DK061002-05
  • Agency: NCI NIH HHS, Id: R29 CA070297
  • Agency: NCI NIH HHS, Id: R29 CA070297-03
  • Agency: NCI NIH HHS, Id: R29 CA070297-05
  • Agency: NCI NIH HHS, Id: R29 CA070297-05S1
  • Agency: NIDDK NIH HHS, Id: R56 DK061002
  • Agency: NIDDK NIH HHS, Id: R56 DK061002-06A1

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Binding Sites
  • COS Cells
  • Cell Cycle
  • Cell Nucleus
  • DNA
  • DNA, Complementary
  • Estradiol
  • Estrogen Receptor alpha
  • Estrogens
  • Forkhead Transcription Factors
  • Genes, Reporter
  • Glutathione Transferase
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Nuclear Proteins
  • Plasmids
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Estrogen
  • Repressor Proteins
  • Tamoxifen
  • Transcription Factors
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Two-Hybrid System Techniques