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Molecular Endocrinology, doi:10.1210/me.2002-0351
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Molecular Endocrinology 17 (4): 589-599
Copyright © 2003 by The Endocrine Society

Isoform-Selective Interactions between Estrogen Receptors and Steroid Receptor Coactivators Promoted by Estradiol and ErbB-2 Signaling in Living Cells

Yongli Bai and Vincent Giguère

Molecular Oncology Group (Y.B., V.G.), McGill University Health Center, and Departments of Biochemistry, Medicine and Oncology (V.G.), Faculty of Medicine, McGill University, Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Vincent Giguère, Molecular Oncology Group, McGill University Health Centre, Room H5-21, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: vincent.giguere{at}mcgill.ca.

Estrogen receptor (ER){alpha} and -ß interact with a variety of coactivator proteins, most notably members of the steroid receptor coactivator (SRC) family, and these interactions have been shown to be regulated by estrogenic ligands and growth factor signaling. Here, using fluorescence resonance energy transfer (FRET), the selectivity of different stimulants on ER{alpha} and -ß interactions with coactivator receptor interaction domains (RIDs) were examined in living cells. We first show that ER{alpha} and ERß homo- and heterodimers form in vivo independently of the presence of 17ß-estradiol (E2) or antiestrogens. We then demonstrate that E2 enhances interactions between ER{alpha} and the RIDs of SRC-1 and SRC-3, whereas the interaction between ER{alpha} with the SRC-2 RID is ligand independent. The transcriptionally inactive mutant ER{alpha}L539A showed no interaction with all three SRC RIDs. Similarly, treatment with the antagonists 4-hydroxytamoxifen and EM-652 abolished all interactions between ER{alpha} and the SRC RIDs. FRET data also demonstrate that, in contrast to ER{alpha}, ERß interacts with all three SRC RIDs in a ligand-independent manner. However, these interactions were further enhanced or stabilized by E2, whereas the antiestrogen EM-652 abolished all interactions. In the presence of both ER{alpha} and ERß, E2 treatment led to the recruitment of SRC RIDs to the nuclei. Finally, expression of the oncogenic activated ErbB-2/Neu protein specifically enhanced ER{alpha} but not ERß interactions with SRC RIDs to an extent similar to E2-stimulated interactions. In summary, using FRET, we demonstrated preferential interactions between ER isoforms and coactivators upon hormonal treatment and activation of a growth factor signal transduction pathway in living cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Coregulators:   SRC-1  |  GRIP1  |  AIB1
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen



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