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| The EMBO Journal
(2000) 19, 4688–4700, doi:10.1093/emboj/19.17.4688 |
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Identification of a new isoform of the human estrogen receptor-alpha (hER- ) that is encoded by distinct transcripts and that is able to repress hER- activation function 1 |
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| Gilles Flouriot1, 2, Heike Brand1, Stefanie Denger1, Raphaël Metivier2, Martin Kos1, George Reid1, Vera Sonntag-Buck1 and Frank Gannon1 |
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1 EMBL, Meyerhofstra e 1, D-69117 Heidelberg, Germany2 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. |
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| Abstract |
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A new isoform of the human estrogen receptor-alpha (hER-) has been identified and characterized. This 46 kDa isoform (hER46) lacks the N-terminal 173 amino acids present in the previously characterized 66 kDa isoform (hER66). hER46 is encoded by a new class of hER- transcript that lacks the first coding exon (exon 1A) of the ER- gene. We demonstrated that these  1A hER- transcripts originate from the E and F hER- promoters and are produced by the splicing of exon 1E directly to exon 2. Functional analysis of hER46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is an effective ligand-inducible transcription factor. In contrast, hER46 is a powerful inhibitor of hER66 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- DNA-binding site. hER66/hER46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hER46 in cellular proliferation. |
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| Keywords: activation functions, estrogen receptor, gene regulation, isoforms, MCF7 |
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