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

A new isoform of the human estrogen receptor-alpha (hER-alpha) has been ide ntified and characterized. This 46 kDa isoform (hER alpha 46) lacks the N-t erminal 173 amino acids present in the previously characterized 66 kDa isof orm (hER alpha 66). hER alpha 46 is encoded by a new class of hER-alpha tra nscript that lacks the first coding exon (exon 1A) of the ER-alpha gene. We demonstrated that these Delta 1A hER-alpha transcripts originate from the E and F hER-alpha promoters and are produced by the splicing of exon 1E dir ectly to exon 2. Functional analysis of hER alpha 46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is a n effective ligand-inducible transcription factor. In contrast, hER alpha 4 6 is a powerful inhibitor of hER alpha 66 in a cell context where the trans activating function of AF-1 predominates over AF-2. The mechanisms by which the AF-1 dominant-negative action is exerted may involve heterodimerizatio n of the two receptor isoforms and/or direct competition for the ER-alpha D NA-binding site. hER alpha 66/ hER alpha 46 ratios change with the cell gro wth status of the breast carcinoma cell line MCF7, suggesting a role of hER alpha 46 in cellular proliferation.