): Dr. Kakefuda's long term objective is to understand how multiple regulatory inputs are integrated to produce combinatorial control of gene expression. It is this combinatorial complexity that allow for developmental and cellular diversity and function. Her proposed training and studies on combinatorial transcription regulation should allow her to learn how to dissect these complex questions in an attempt to understand fundamental biological mechanisms. D r . Kakefuda's general strategy is to study a combination of well characterized transcription factors, the glucocorticoid receptor and AP-1. The characterization of the collaboration between these regulators at different classes of response elements should reveal how complex cellular events can be regulated by integrating signals through protein-protein and protein-DNA interactions. This project is aimed at defining how the glucocorticoid receptor (GR) can act as both a positive and negative regulator of transcription with nonreceptor factors, such as AP-1, from a complex GR binding promoter element (GRE). Therefore, the candidate will functionally dissect the transcriptional regulatory domain of GR, characterize GR-associated proteins involved in the transcriptional regulation, and define the elements in the GRE that influence the activity of GR. She proposes three specific aims:
Aim 1. What are the regions in the N-terminal transcriptional regulatory domain of GR that mediate activation and repression at composite and tethering GREs? Aim 2. How do interactions, both intramolecular and with nonreceptor factors, specify positive or negative regulation by the N-terminal transcriptional regulatory domain of GR? Aim 3. How does the GRE sequence influence transcriptional regulatory activity of GR?
