Objectif Estrogen receptors (ERalpha and ERbeta) function as ligand-regulated transcription factors that mediate the physiological effects of estrogen hormones. In addition to ligands, the activities of ERs can be modulated by post-translational modification. ERalpha (ERa), for example, is subject to phosphorylation, ubiquitylation, sumoylation, and acetylation.Recently, the Kraus lab has identified two lysine residues in ERa that are the sites of acetylation by the p300 acetyltransferase. The lab has also shown that acetylation of these lysins by p300 increases the DNA binding and transactivation activities of ERa. Although these initial results establish a role for acetylation in regulating the activity of ERa, additional studies are needed to clarify the role of acetylation in ERa biology.The broad hypothesis of my proposed studies is that transcriptional outcomes in estrogen signalling pathways are ultimately determined by receptor and accessory factors, including the covalent modification state of ER and the cell type-specific repertoire of enzymes that control those modifications.More specifically, I hypothesize that acetylation of ERa has the potential to impact the molecular activity of the receptor at enhancer elements, response to ligands, crosstalk with other signalling pathways, and ultimately gene regulation in estrogen signalling pathways.In this proposal, I outline a series of experiments using biochemical, cell-based, and genomic approaches in both cell and animal models in order to determine the:- Effects of ERa acetylation on estrogen-regulated gene expression,- Mechanisms of ERa acetylation/deacetylation, and- Effects ERa acetylation on the mitogenic and tumourigenic effects of estrogens, and the antagonistic actions of SERMs.Collectively, these studies will shed new light on the regulation of ERa function in the estrogen signalling pathways and may suggest new ways to target the receptor for therapeutic purposes. Champ scientifique natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Mots‑clés acetylation estrogen receptor gene regulation post-translational modifications Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Thème(s) MOBILITY-2.2 - Marie Curie Outgoing International Fellowships (OIF) Appel à propositions FP6-2005-MOBILITY-6 Voir d’autres projets de cet appel Régime de financement OIF - Marie Curie actions-Outgoing International Fellowships Coordinateur KAROLINSKA INSTITUTET Contribution de l’UE Aucune donnée Adresse Nobels väg 5 STOCKHOLM Suède Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée Participants (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire CORNELL UNIVERSITY, ITHACA États-Unis Contribution de l’UE Aucune donnée Adresse 120 Day Hall ITHACA Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée
