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Effects of Multiple Estrogen Responsive Elements on the Actions of Estradiol and Tamoxifen.

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Annual rept. 1 Jul 98-30 Jun 99

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Multiple copies of estrogen responsive elements, EREs, located in the regulatory regions of highly estrogen responsive genes, synergistically regulate their gene expression. We and others previously reported that the number, location and spacing of multiple EREs influence the extent of synergy at a given promoter. Based on a model that protein-protein interactions mediate the synergy at multiple EREs, we have begun to dissect the estrogen receptor, ER alpha, to identify a region in the receptor that is directly involved in the synergy function. Previous reports have demonstrated that ER activation functions AF-1 and AF-2, located at the N- and C-terminus, respectively, of ER are specific to cell and promoter contexts. We therefore used a minimal TATA box promoter to analyze synergy mediated by ER, in the absence of other transcription factors. In COS-1 cells, AF-1 of ER alpha in the context of a full length receptor, is required for synergy at multiple EREs. It appears that both the sub domains of AF-1 aa 41-64 and 87-108 are required for synergy when AF-2 is mutated. We propose to examine whether tamoxifen can mediate synergy under similar conditions. Since tamoxifen agonism appears to be promoter dependent, various promoter contexts will be utilized to compare the effects of estradiol and tamoxifen.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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