The association of ligand with the estrogen receptor (ER) induces a conformational change in the protein structure which initiates a cascade of molecular events, that lead ultimately to an association of ER with the regulatory regions within target genes. The transcriptional effect of the DNA-hound receptor is determined by cellular and promoter context. Accumulated biochemical and genetic evidence has suggested that up to the point of ER-DNA interaction that ER agonists and antagonists function in a very similar manner promoting dimerization, high affinity DNA binding and alterations in chromatin structure. It is likely therefore, that antiestrogens such as tamoxifen, exert their biological effects on a process downstream of the receptor-DNA interaction. We have reconstituted an estrogen responsive transcription system in yeast and mammalian cells and have identified one genetic locus (SSN6) which when mutated allows receptor antagonists to function as agonists. We propose in this study to use similar genetic approaches to identify additional cellular proteins required to distinguish between ER agonists and antagonists and evaluate the role of these loci (and SSN6) on ER function. In addition, we propose to delineate the structural regions in ER that interface with these accessory proteins. We feel that the development of cellular resistance to tamoxifen may result from alterations in the way the cellular transcription apparatus recognizes the tamoxifen-ER complex. We hypothesize that alterations in the expression level or genetic alterations in the proteins that constitute the basal transcription apparatus can determine whether tamoxifen will function as a receptor antagonist or not.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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Margolis, Ronald N
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Duke University
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United States
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