Adjunct Professor Emeritus
Pediatrics/ Biochemistry & Biophysics
Cancer Cell Biology
Area of interest
Mechanisms of androgen action in development and prostate cancer
Androgen action is mediated through the androgen receptor by binding with high affinity testosterone or dihydrotestosterone causing receptor dimerization and binding to specific DNA sequences in androgen regulated genes. Recent evidence indicates that androgen receptor dimerization involves an androgen dependent amino- and carboxyl-terminal (N/C) interaction that occurs bimolecularly independent of the AR DNA binding domain. This N/C interaction reduces the disassociation rate of bound androgen, slows the receptor degradation rate, and is required for androgen action at low circulating androgen concentrations. Recent studies on activation function 2 in the ligand binding domain of the androgen receptor have demonstrated that AF2 is the interaction site for the NH2-temrinal domain but only weakly interacts with the p160 coactivators. The studies raise the possibility that the N/C interaction contributes to androgen specificity of the androgen receptor and to inhibition of the interaction of the p160 coactivators with this region of the ligand binding domain. Two LxxLL-like motifs in the androgen receptor, FQNLF and WHTLF, were identified that mediate the N/C interaction with the AF2 region of the ligand binding domain. Other recent work is focused on the molecular mechanisms of androgen action in prostate cancer. In collaborative studies with Drs. James L. Mohler, Frank S. French and Christopher W. Gregory, we have observed changes in the androgen receptor with the onset of androgen insensitive prostate cancer. These exciting studies in progress offer the potential for new therapeutic approaches for the treatment of prostate cancer. Other studies focus on the presence of environment androgens. In collaboration with Dr. Ronald Jenkins at the University of Alabama in Birmingham, we have discovered environmental androgens in the Fenholloway River water downstream of a polluting paper mill. Female fish in this river are masculinized due to contaminating androgens. While one androgen has been identified, studies are ongoing to identify additional chemicals from the river with androgen activity. The studies demonstrate that chemicals polluting the environment can interact with the endocrine system. These so-called endocrine disruptors activate or inhibit endocrine pathways. Environmental chemicals have now been identified that influence the androgen receptor by acting as antagonists or agonists. In other studies, the androgen receptor has been purified and collaborative studies are in progress with Dr. Charles Carter in the Biochemistry Department to establish the crystal structure of the androgen receptor bound to DNA.