Transcriptional activity of human brain estrogen receptor-α splice variants: Evidence for cell type-specific regulation

Estrogen receptor alpha (ER alpha) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ER alpha splice variants from this group with different molecular defects: MB1 (intron retention), TADDI (small deletion between exons 3 and 4 with an insert), the Delta (deletion) 3*-7*/819 (complete skipping of exons 4, 5 and 6 and partial deletion of exons 3 and 7) and the Delta 3-6 (lacking exons 3, 4, 5 and 6) in HeLa and M17 cells upon stimulation with (17 beta)estradiol or insulin-like growth factor 1 (IGF-1). In HeLa cells, all these splice variants showed the dominant negative function that was more pronounced for the TADDI. In M17 cells the dominant negative variants appeared to be the MB1 and the Delta 3-6, whereas TADDI turned out to be a clearly dominant positive variant. In M17 cells mRNA levels of Delta 3-6 and Delta 3*-7*/819 variants increased following (17 beta)estradiol administration. In Hela cells (17 beta)estradiol up-regulated the IGF-1 receptor mRNA levels in cultures transfected with MB1, TADDI and Delta 3*-7*/819. Our data demonstrate that ER alpha splice variants show differential levels of the transcriptional activity in a cell type-specific way and that IGF-1 signaling pathways are differentially employed in a cell-type specific manner depending on the level of the discrete ER alpha splice variants expressed. Functional properties of various ER alpha splice variants and their cell type-specificity should, thus, be considered as potential confounders of estrogen therapy effects on the brain. (C) 2013 Elsevier B.V. All rights reserved.