ER ACETYLATION · Functional consequences of estrogen receptor alpha acetylation in hormone-regulated transcription

Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.

Project objective

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.

Original text from CORDIS.

Participants

• KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
• CORNELL UNIVERSITY, ITHACA · ITHACACity levelUnited States

Links

• View on CORDIS