University of Virginia Health System

The estrogen receptor, a member of the steroid hormone receptor superfamily, can be activated as a transcription factor by its natural ligands, the estrogens, or by a variety of non-steroidal agents. The estrogen receptor is known to be involved in a large percentage of breast cancers and therefore, the overall objective of the first goal in the laboratory is to identify therapeutic targets to control inappropriate transcription by the estrogen receptor. Identification of a common component in the mechanism of transcriptional activation by estradiol and the various non-steroidal agents that activate estrogen receptor-dependent transcription would greatly aid in developing new treatments for breast cancer.

Presently, we have determined that phosphorylation of Serine 118 in the human estrogen receptor appears to be a common event that occurs upon treatment with a variety of agents. We are currently attempting to understand the role Serine 118 phosphorylation plays in the activation of transcription and to identify and characterize the kinase and phosphatase that are involved in this phosphorylation.

Additionally, we are interested in the regulation of estrogen receptor function by the MAPK pathway. The p90 ribosomal S6 kinase family (Rsk) are effectors of MAPK. We have found that Rsk phosphorylates Serine 167 in the human estrogen receptor. Serine 167 phosphorylation is important in activation of estrogen receptor-mediated transcription in response to EGF.

Biosensor Development

The aim of our research is to develop new biosensors to detect selected organic compounds that might be present at low concentrations in complex mixtures such as urine, ground water and soil. The principle of the approach is to use in vitro evolution of a naturally occuring protein-based biosensor, to create ones with new specificities. Using the power of yeast genetics and modern molecular biology, modifications and further refinements of identified biosensors can be easily and cheaply performed.

Current efforts focus on identifying biosensors that specifically recognize pesticides and explosive residues.

Bioscreening

PharmaBiologicals is a novel program that offers a unique opportunity for fellows and students to learn about the process of drug discovery outside of an industry setting. We are developing high-throughput robotic screening (HTS) assays to discover bioactive, naturally-occurring molecules. Protein kinases, that are known to modulate specific cell biological processes, are the primary targets.