Bryce M. Paschal, PhD
Nuclear import of androgen receptor as a target for chemotherapy in prostate cancer
The Paschal laboratory studies how nuclear transport and signal transduction control the compartmentalization and activity of transcription factors, particularly in the context of prostate cancer. A major focus of these studies is the androgen receptor (AR), a steroid hormone receptor that is critical for prostate cell growth. AR regulates the expression of >100 genes in the prostate, and is an important target of current prostate cancer therapies. AR must undergo nuclear import in order to function as a transcription factor, a process that is normally regulated by androgen. There is compelling evidence, however, that AR acquires the ability to undergo androgen-independent import in advanced prostate cancer. Defining the underlying transport mechanism could open the door to new strategies for inhibiting AR activity in proliferating prostate cells.
AR is the target of multiple kinases, and in collaboration with Dr. Michael Weber, phospho-site antibodies have been generated to study the pathways and functions of phospho-regulation of AR. In the course of these studies, our laboratory discovered a novel mechanism for loading protein phosphatase 2A (PP2A) onto AR. PP2A loading onto AR results in rapid dephosphorylation of five phospho-serines within a domain that is critical for the transcription function of AR. The PP2A loading mechanism requires small t antigen, a product encoded by SV40 that binds and alters the structure of a PP2A subunit. Experiments in collaboration with Dr. David Brautigan are aimed at defining the structural basis of the PP2A loading reaction, as well as determining the cellular factors that mediate PP2A loading onto AR. Mechanistic studies on AR compartmentalization and activity are performed primarily in two systems: prostate cancer cell lines and human tumors propagated as xenografts in mice. Information gained from these systems (which are amenable to experimental manipulation) provides the conceptual framework for analyzing prostate cancer patient samples. The goal of these translational studies is to correlate molecular changes in AR and signal transduction pathways with prostate cancer disease progression. Patient sample analysis is being performed in collaboration with Drs. Henry Frierson and Dan Theodorescu.