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Regulation of Transcriptional Co-Activators by Environmental EstrogensMark Bedford, Ph.D. Project DescriptionNuclear hormone receptor activity is regulated by accessory proteins such as histone acetyltransferases and arginine methyltransferases, that function as coactivators for these receptors and such are involved in hormone responsive tumor progression. This activity is facilitated in part by the ability of the protein arginine methyltransferases (PRMTs), PRMT1 and CARM1, to methylate histones in vivo and these coactivators are potential targets for drug development. Xenoestrogens are compounds of plant or synthetic origin that often share structural similarity with the principal mammalian estrogen, 17a-estradiol. Recently, a high throughput screen for small-molecule inhibitors of the PRMT sub-class of coactivators was performed. The majority of these inhibitors were polyphenols, and one in particular (AMI-18) shared additional features with a group of xenoestrogens. Thus a panel of xenoestrogens was tested and a large number of them found to inhibit PRMT activity in vitro. In this study, the intent is to evaluate the ability of xenoestrogens and SERMs to regulate methyltransferase and acetyltransferase activities of recombinant proteins and in cells. Techniques to be used will include in vitro methylation assays, transcriptional reporter assays, chromatin precipitation (ChIP) experiments and RT-PCR. In this exploratory/developmental research project the novel idea that some xenoestrogens posses the ability to both bind the estrogen receptor (ER) (thus perturbing transcription) and inhibit co-activator activity (thereby suppressing transcription) will be investigated. This raises the possibility that combination treatment with the best antagonists and the best co-activator inhibitors may be of therapeutic value particularly for hormone-dependent tumors, like breast and prostate cancers. The specific aims are to characterize:
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