Identification of a new isoform of the human estrogen receptor‐alpha (hER‐α) that is encoded by distinct transcripts and that is able to repress hER‐α activation function 1

Abstract

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