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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Heterodimeric Complex
Molecular Oncology Group,
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), ER
and ER
, 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
ER
-ER
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 ER
-ER
heterodimer: the mixed agonist-antagonist 4-hydroxytamoxifen acts as an agonist in a promoter- and cell context-dependent manner via the ER
AF-1, while activation of the
complex by the mitogen-activated protein kinase (MAPK) pathway requires
only the ER
- or ER
-responsive MAPK site. Using ligand-binding and
AF-2-defective mutants, we further demonstrated that while the
ER
-ER
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 ER
-ER
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.
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