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Molecular and Cellular Biology, March 1999, p. 1919-1927, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor alpha -beta Heterodimeric Complex

Gilles B. Tremblay,1 André Tremblay,1 Fernand Labrie,2 and Vincent Giguère1,3,*

Molecular Oncology Group, McGill University Health Center,1 and Departments of Biochemistry, Medicine and Oncology, McGill University,3 Montréal, and Laboratory of Molecular Endocrinology, Laval University Medical Research Center and Laval University, Québec,2 Québec, Canada

Received 16 October 1998/Returned for modification 19 November 1998/Accepted 1 December 1998

Estrogenic responses are now known to be mediated by two forms of estrogen receptors (ER), ERalpha and ERbeta , that can function as homodimers or heterodimers. As homodimers the two have been recently shown to exhibit distinct transcriptional responses to estradiol (E2), antiestrogens, and coactivators, suggesting that the ER complexes are not functionally equivalent. However, because the three possible configurations of ER complexes all recognize the same estrogen response element, it has not been possible to evaluate the transcriptional properties of the ER heterodimer complex by transfection assays. Using ER subunits with modified DNA recognition specificity, we were able to measure the transcriptional properties of ERalpha -ERbeta heterodimers in transfected cells without interference from the two ER homodimer complexes. We first demonstrated that the individual activation function 1 (AF-1) domains act in a dominant manner within the ERalpha -ERbeta heterodimer: the mixed agonist-antagonist 4-hydroxytamoxifen acts as an agonist in a promoter- and cell context-dependent manner via the ERalpha AF-1, while activation of the complex by the mitogen-activated protein kinase (MAPK) pathway requires only the ERalpha - or ERbeta -responsive MAPK site. Using ligand-binding and AF-2-defective mutants, we further demonstrated that while the ERalpha -ERbeta heterodimer can be activated when only one E2-binding competent partner is present per dimer, two functional AF-2 domains are required for transcriptional activity. Taken together, the results of this study of a retinoid X receptor-independent heterodimer complex, the first such study, provide evidence of different stoichiometric requirements for AF-1 and -2 activity and demonstrate that AF-1 receptor-specific properties are maintained within the ERalpha -ERbeta heterodimer.

* Corresponding author. Mailing address: Molecular Oncology Group, Royal Victoria Hospital, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1. Phone: (514) 843-1479. Fax: (514) 843-1478. E-mail: vgiguere{at}dir.molonc.mcgill.ca.

Molecular and Cellular Biology, March 1999, p. 1919-1927, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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