SKF-82958 is a subtype-selective estrogen receptor-alpha (ERalpha ) agonist that induces functional interactions between ERalpha and AP-1.
The transcriptional activity of estrogen receptors (ERs) can be regulated by ligands as well as agents such as dopamine, which stimulate intracellular signaling pathways able to communicate with these receptors. We examined the ability of SKF-82958 (SKF), a previously characterized full dopamine D1 receptor agonist, to stimulate the transcriptional activity of ERalpha and ERbeta. Treatment of HeLa cells with SKF-82958 stimulated robust ERalpha-dependent transcription from an estrogen-response element-E1b-CAT reporter in the absence of estrogen, and this was accompanied by increased receptor phosphorylation. However, induction of ERbeta-directed gene expression under the same conditions was negligible. In our cell model, SKF treatment did not elevate cAMP levels nor enhance transcription from a cAMP-response element-linked reporter. Control studies revealed that SKF-82958, but not dopamine, competes with 17beta-estradiol for binding to ERalpha or ERbeta with comparable relative binding affinities. Therefore, SKF-82958 is an ERalpha-selective agonist. Transcriptional activation of ERalpha by SKF was more potent than expected from its relative binding activity, and further examination revealed that this synthetic compound induced expression of an AP-1 target gene in a tetradecanoylphorbol-13-acetate-response element (TRE)-dependent manner. A putative TRE site upstream of the estrogen-response element and the amino-terminal domain of the receptor contributed to, but were not required for, SKF-induced expression of an ERalpha-dependent reporter gene. Overexpression of the AP-1 protein c-Jun, but not c-Fos, strongly enhanced SKF-induced ERalpha target gene expression but only when the TRE was present. These studies provide information on the ability of a ligand that weakly stimulates ERalpha to yield strong stimulation of ERalpha-dependent gene expression through cross-talk with other intracellular signaling pathways producing a robust combinatorial response within the cell.
Walters
Marian R
MR
Department of Physiology, Tulane Medical School, New Orleans, Louisiana 70112, USA.
Dutertre
Martin
M
Smith
Carolyn L
CL
D001483:Base Sequence; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D017931:DNA Primers; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D001552:Benzazepines; D017931:DNA Primers; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; C071262:SK&F 82958