Open AccessModulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone.
Author(s) -
Carolyn L. Smith,
Orla M. Conneely,
Bert W. O’Malley
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.13.6120
Subject(s) - dopamine , dopaminergic , receptor , estrogen receptor , dopamine receptor , biology , microbiology and biotechnology , chloramphenicol acetyltransferase , mutant , reporter gene , ligand (biochemistry) , medicine , transgene , endocrinology , chemistry , gene expression , biochemistry , gene , genetics , cancer , breast cancer
It has been previously demonstrated that several members of the steroid receptor superfamily may be activated by the neurotransmitter dopamine in the apparent absence of cognate ligand. We have examined wild-type and mutant human estrogen receptors (ERs, [Gly400]ER and [Val400]ER, respectively) for their abilities to activate ER-dependent transcription of a transgene in a ligand-independent manner. In cells expressing the wild-type ER, dopamine was nearly as effective as 17 beta-estradiol at inducing the chloramphenicol acetyltransferase activity of the reporter gene in a dose-dependent manner; simultaneous addition of suboptimal concentrations of 17 beta-estradiol and dopamine stimulated transcription more than either compound alone. Dopamine alone was unable to induce gene expression in cells expressing [Val400]ER mutant receptors, but concomitant treatment with 17 beta-estradiol produced a synergistic increase in transcription, suggesting that the ligand may alter the mutant receptor's conformation such that it can be activated subsequently by a dopaminergic signaling mechanism. In the presence of the antiestrogen ICI 164,384, dopamine-stimulated gene expression was undetectable in cells expressing either form of ER. However, simultaneous treatment of cells expressing wild-type ER with trans-4-hydroxytamoxifen and dopamine resulted in transgene expression that was additive in nature compared to either compound alone; similar treatment of cells expressing [Val400]ER produced a synergistic increase. Our results suggest that ligand and ligand-independent activation of the ER initiate from distinct pathways and that the latter may occur in a variety of target tissues subject to modulation by receptor ligands.