Emily B. Askew
3336 MBRB
Chapel Hill, NC 37599
Tel: (919) 966-0929
Fax: (919) 966-2203
Education
Doctorate of Philosophy
Curriculum in Toxicology
Research Advisor: Dr. Elizabeth M. Wilson
Date of Matriculation: 2003
Bachelor of Science in Biology
University of North Carolina at Chapel Hill, May 2003
Publications and Recent Abstracts
Askew, E. B., Gampe, Jr., R. T., Stanley, T. B., Faggart, J. L., and Wilson, E. M. (2007) Modulation of androgen receptor activation function two by testosterone and dihydrotestosterone. J Biol Chem. *35*, 25801-25816
Awards
2007 Department of Defense Prostate Cancer Pre-Doctoral Training Grant
Dissertation
“Modulation of Androgen Receptor Activity in Normal and Neoplastic Prostate”
Advisor: Dr. Elizabeth M. Wilson
The androgen receptor (AR) is a member of the nuclear receptor superfamily of ligand activated transcription factors. Androgen activation of AR is involved in prostate growth, bone and muscle mass, spermatogenesis and is a predisposing factor in prostate cancer. Unlike other nuclear receptors, AR binds two biologically active androgens, testosterone (T) and dihydrotestosterone (DHT) with similar high affinity yet the basis for the different potencies of T and DHT remains unresolved. AR contains activation function 1 (AF1) that is located in the largely unstructured NH2-terminal region and activation function 2 (AF2) within the LBD that requires androgen binding for its structural integrity. In AR, androgen binding completes the AF2 docking site, allowing for LXXLL-related motif binding. Furthermore, AR AF2 binding to the AR 23FQNLF27 FXXLF motif completes the androgen dependent AR NH2-and carboxyl-terminal AR N/C interaction that is critical for androgen regulated gene transcription.
Previous work from our laboratory suggests that AF2 is critical to AR function in prostate cancer cells and is selectively regulated through several mechanisms. Elevated levels of endogenous coactivators are found in a majority of prostate cancer specimens, and the AR specific coactivator, melanoma antigen gene protein-11 (MAGE-11), supports AF2 activity in benign as well as cancerous tissues. Below the surface of AF2 is an interface which provides for structural communication between the bound ligand and AF2 as evident in the fact that AR AF2 binding to the AR FXXLF motif slows androgen dissociation while somatic prostate cancer mutations in and around the AF2 site are capable of enhancing AR function in vivo without altering agonist binding affinity. It is critical to understand the structure function properties that underlie increased AR AF2 activity in prostate neoplasia in order to design more potent drug therapies to combat cancer recurrence in light of current therapies which are not curative.
My thesis proposal pursues these and additional recent findings for a novel interaction surface on the AR LBD that modulates AF2 activity. My plan is to first identify the structural and functional mechanisms which underlie the disparity between T and DHT mediated AR transactivation as well as AR AF2 motif binding in normal prostate and prostate cancer. Additionally, I will characterize a new binding site in the AR LBD by performing structure studies and establish the functional consequences of the AR N/C interaction on AR binding to androgen response element (ARE) DNA. I plan to determine the structural consequences of the AR N/C interaction on AF2 activity and AR binding to ARE DNA by determining the crystal structure of an AR deletion mutant in the absence and presence of ARE DNA.
Personal Interests
Teaching, Carolina Sports, The Beach, Eastern NC BBQ and Sweet Tea!