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School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, Scotland, United Kingdom AB25 2ZD
Address all correspondence and requests for reprints to: Dr. Iain J. McEwan, School of Medical Sciences, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom AB25 2ZD. E-mail: iain.mcewan{at}abdn.ac.uk.
The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. The AR functions as a ligand-activated transcription factor in the presence of the cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized a highly conserved sequence at the C-terminal end of helix 10/11 in the ligand-binding domain (LBD), which is prone to receptor point mutations in prostate cancer. This sequence includes threonine 877 that is involved in hydrogen bonding to the D ring of the steroid molecule and leads to promiscuous ligand activation of the AR when mutated to alanine or serine. A second mutation in this region, H874Y, also results in a receptor protein that has broadened ligand-binding specificity, but retains an affinity for DHT (Kd = 0.77 nM) similar to that of the wild-type receptor. The structure of the mutant LBD, expressed in Escherichia coli, is not dramatically altered compared with the wild-type AR-LBD in the presence of DHT, but shows a modestly increased sensitivity to protease digestion in the absence of hormone. This mutant AR showed wild-type AR-LBD/N-terminal domain interactions, but significantly enhanced binding and transactivation activity with all three members of the p160 family of coactivator proteins. Together, these phenotypic changes are likely to confer a selective advantage for tumor cells in a low androgen environment resulting from hormone therapy.
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