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Novel Strategies for the Identification and Characterization of Selective Estrogen Receptor Modulators (SERMs)

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Annual rept. 24 Sep 2002-23 Sep 2003

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Estrogens promote growth of certain breast endometrial cancers. Selective estrogen receptor modulators SERMs, ligands that block the activity of estrogen in only selective tissues, allow to control the growth of these cancers while avoiding the many unwanted side effects associated with the use of antiestrogens. The goal of our work is to identify the mechanisms that control the activity of SERMs and to develop efficient high-throughput strategies for the identification of novel SERMs. SERMs exert their activities by binding to the two estrogen receptors, Era and ERb. Ligand binding changes the position of a-helix 12 H12 in the ER ligand-binding domain and regulates the interaction of ERs with cellular coactivators and corepressors. Previously, we identified that the F-domain, a receptor-specific domain that follows H12, contributes to coactivator binding and specificity of Era but not ERb. We have continued these studies by analyzing the role of the F-domain in SERM-and corepressor binding and in modulating the transcriptional response to hormone. Moreover, we have identified and optimized a strategy to introduce fluorescence labels into H12 or the F-domain. These fluorescent receptors will allow us to monitor the dynamics and structural reorganization of ER upon SERM binding.

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  • Biochemistry
  • Medicine and Medical Research

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