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Article
The EMBO Journal (2000) 19, 4688–4700, doi:10.1093/emboj/19.17.4688
Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1
Gilles Flouriot1, 2, Heike Brand1, Stefanie Denger1, Raphaël Metivier2, Martin Kos1, George Reid1, Vera Sonntag-Buck1 and Frank Gannon1
1 EMBL, Meyerhofstras zlige 1, D-69117 Heidelberg, Germany
2 Endocrinologie Moléculaire de la Reproduction, UPRES-A CNRS 6026, Campus de Beaulieu, 35042 Rennes cedex, France

To whom correspondence should be addressed
Frank Gannon, Gannon@EMBL-Heidelberg.de

Received 25 January 2000; Revised 3 July 2000; Accepted 4 July 2000.
Abstract
A new isoform of the human estrogen receptor-alpha (hER-alpha) has been identified and characterized. This 46 kDa isoform (hERalpha46) lacks the N-terminal 173 amino acids present in the previously characterized 66 kDa isoform (hERalpha66). hERalpha46 is encoded by a new class of hER-alpha transcript that lacks the first coding exon (exon 1A) of the ER-alpha gene. We demonstrated that these Delta1A hER-alpha transcripts originate from the E and F hER-alpha promoters and are produced by the splicing of exon 1E directly to exon 2. Functional analysis of hERalpha46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is an effective ligand-inducible transcription factor. In contrast, hERalpha46 is a powerful inhibitor of hERalpha66 in a cell context where the transactivating function of AF-1 predominates over AF-2. The mechanisms by which the AF-1 dominant-negative action is exerted may involve heterodimeri zation of the two receptor isoforms and/or direct competition for the ER-alpha DNA-binding site. hERalpha66/hERalpha46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hERalpha46 in cellular proliferation.
Keywords: activation functions, estrogen receptor, gene regulation, isoforms, MCF7
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