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J Biol Chem, Vol. 274, Issue 36, 25756-25768, September 3, 1999

Cooperative Assembly of Androgen Receptor into a Nucleoprotein Complex That Regulates the Prostate-specific Antigen Enhancer

Weibiao Huang, Yuriy Shostak, Paul Tarr, Charles Sawyers, and Michael Carey

From the  Department of Biological Chemistry, Box 1737, and  Department of Medicine, Box 1678, UCLA School of Medicine, Los Angeles, California 90095

Prostate cancer is characterized by elevated serum levels of prostate-specific antigen (PSA). PSA gene expression is controlled by an androgen-responsive transcriptional enhancer. Our study suggests that formation of a nucleoprotein complex, encompassing 170 base pairs of enhancer DNA, mediates androgen-responsive PSA enhancer activity. The complex is assembled by cooperative binding of androgen receptor to at least four tandem, nonconsensus androgen response elements (AREs). Systematic mutagenesis of the AREs demonstrated that they act synergistically to stimulate androgen receptor-responsive gene expression. We discuss a mechanism whereby a combination of high androgen receptor levels in the prostate and low affinity AREs contribute to the cell type specificity and activity of the enhancer.

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