title: Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone.
abstract: 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.
authors.affiliation: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030-3498.
authors.forename: C L
authors.initials: CL
authors.lastname: Smith
authors.forename: O M
authors.initials: OM
authors.lastname: Conneely
authors.forename: B W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004298:Dopamine / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D053284:Polyunsaturated Alkamides; D011954:Receptors, Dopamine / Q000502:physiology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; D008024:Ligands; D053284:Polyunsaturated Alkamides; D011954:Receptors, Dopamine; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C051781:ICI 164384; D015500:Chloramphenicol O-Acetyltransferase; D004298:Dopamine