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Estrogen Receptor (ER) ß Modulates ER-Mediated Transcriptional Activation by Altering the Recruitment of c-Fos and c-Jun to Estrogen-Responsive Promoters

Department of Biosciences at Novum (J.M., B.W., M.T., J.W., A.S., J.-Å.G.), Karolinska Institutet, Novum, S-14157 Huddinge, Sweden; and Department of Medical Nutrition (J.-Å.G.), Karolinska Institutet, Novum, S-14186 Huddinge, Sweden

Address all correspondence and requests for reprints to: Jason Matthews, Ph.D., Department of Biosciences at Novum, Karolinska Institutet, Huddinge 14157, Sweden. E-mail: jason.matthews{at}biosci.ki.se.

In this study, an estrogen receptor (ER) -expressing T47D cell line containing an inducible tet-off FLAG-ERß was used to examine the influence of ERß on ER activity. Real-time PCR analysis of mRNA levels of two well-studied estrogen-responsive genes, pS2 and progesterone receptor (PR), showed that the expression levels of both genes were reduced in the presence of ERß. Chromatin immunoprecipitation assays showed that the 17ß-estradiol (E2)-induced recruitment patterns to the pS2 and PR promoters were similar for both ER and ERß. ERß expression did not significantly influence the kinetic recruitment profile of ER to the pS2 promoter, but it was evident that ER occupancy at the PR promoter was reduced. The E2-induced recruitment of c-Fos to a 12-O-tetradecanoylphorbol-13-acetate response element site in the PR promoter was significantly reduced in the presence of ERß, whereas only a slight reduction in the recruitment of c-Fos to the pS2 promoter was observed. ERß expression resulted in a significant reduction in the E2-induced expression of c-Fos mRNA. The recruitment pattern of c-Jun was also altered by ERß, although the expression levels of c-Jun were not. Expression of ERß caused a further 30–50% decrease of the E2-induced reduction in ER protein after 3 h of E2 treatment, showing that ERß influences ER protein levels. The altered recruitment of the activating protein-1 complex, combined with the reduction in ER protein levels, may partly explain the antagonistic effect of ERß on ER-mediated transcription.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  PR

Coregulators:   CBP

Ligands:   17β-Estradiol

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