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Molecular Endocrinology 13 (1): 129-137
Copyright © 1999 by The Endocrine Society

Functional Analysis of a Novel Estrogen Receptor-ß Isoform

Bettina Hanstein1, Hong Liu2, Molly C. Yancisin and Myles Brown

Department of Adult Oncology Dana-Farber Cancer Institute Boston, Massachusetts 02115

A new level of complexity has recently been added to estrogen signaling with the identification of a second estrogen receptor, ERß. By screening a rat prostate cDNA library, we detected ERß as well as a novel isoform that we termed ERß2. ERß2 contains an in-frame inserted exon of 54 nucleotides that results in the predicted insertion of 18 amino acids within the ERß hormone-binding domain. We also have evidence for the expression of both ERß1 and ERß2 in human cell lines. Competition ligand binding analysis of bacterially expressed fusion proteins revealed an 8-fold lower affinity of ERß2 for 17ß-estradiol (E2) [dissociation constant (Kd ~ 8 nM)] as compared with ERß1 (Kd ~ 1 nM). In vitro transcribed and translated ERß1 and ERß2 bind specifically to a consensus estrogen responsive element in a gel mobility shift assay. Furthermore, we show heterodimerization of ERß1 and ERß2 with each other as well as with ER{alpha}. In affinity interaction assays for proteins that associate specifically with the hormone-binding domain of these receptors, we demonstrate that the steroid receptor coactivator SRC-1 interacts in an estrogen-dependent manner with ER{alpha} and ERß1, but not with ERß2. In cotransfection experiments with expression plasmids for ER{alpha}, ERß1, and ERß2 and an estrogen-responsive element-containing luciferase reporter, the dose response of ERß1 to E2 was similar to that of ER{alpha} although the maximal stimulation was approximately 50%. In contrast, ERß2 required 100- to 1000-fold greater E2 concentrations for maximal activation. Thus, ERß2 adds yet another facet to the possible cellular responses to estrogen.




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