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J. Biol. Chem., Vol. 280, Issue 13, 13097-13104, April 1, 2005
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Is Dependent on Ca2+/Calmodulin*
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
Estrogen binds to estrogen receptors in cells, thereby activating the receptors and eliciting biological effects. One of the best characterized effects of estrogen receptor-
(ER) is transcriptional activation that regulates selected target genes in the nucleus. Work from several laboratories has documented a Ca2+-dependent interaction between ER and calmodulin. In addition, we previously showed that antagonism of calmodulin function in cells prevented estradiol from inducing ER transcriptional activity, suggesting that association of ER with calmodulin participates in ER function. In this study we adopted a multifaceted approach to directly address this hypothesis. The calmodulin binding domain on ER was identified and several mutant ER constructs unable to bind calmodulin were generated. Elimination of calmodulin binding prevented estradiol from stimulating ER transcriptional activation. Essentially identical results were obtained when intracellular Ca2+ was chelated with the cell-permeable chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM). Moreover, CaM1234, a calmodulin mutant that is unable to bind Ca2+, functioned as a dominant negative construct. Transfection of cells with CaM1234 reduced estradiol-stimulated ER transcriptional activity. These data indicate that binding to calmodulin is required for normal transcriptional function of ER.
Received for publication, September 15, 2004 , and in revised form, January 3, 2005.
* This work was supported in part by United States Army Grant DAMD 17-02-1-0305, National Institutes of Health Grant CA93645 (to D. B. S.), and a Susan G. Komen Breast Cancer Foundation Grant (to L. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Brigham and Women's Hospital, Thorn 530, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6627; Fax: 617-278-6921; E-mail: dsacks{at}rics.bwh.harvard.edu.
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