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Identification of an Androgen-Dependent Enhancer within the Prostate Stem Cell Antigen Gene

Departments of Urology (A.J., R.E.R.), Biological Chemistry (A.L., M.F.C.), and Medicine (I.V.), and Molecular Biology Institute (M.F.C., R.E.R.), UCLA School of Medicine, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Dr. Michael F. Carey, Department of Biological Chemistry, UCLA School of Medicine, Box 951737, Los Angeles, California 90095. E-mail: mcarey{at}mednet.ucla.edu.

Prostate stem cell antigen (PSCA) is emerging as an important diagnostic marker and therapeutic target in prostate cancer. Previous studies indicated that PSCA was directly regulated by androgens, but the mechanism has not been elucidated. Here we describe the identification of a compact cell-specific and androgen-responsive enhancer between 2.7 and 3 kb upstream of the transcription start site. The enhancer functions autonomously when positioned immediately adjacent to a minimal promoter. Deoxyribonuclease I footprinting analysis with recombinant androgen receptor (AR) reveals that the enhancer contains two AR binding sites at one end. Mutational analysis of the AR binding sites revealed the importance of the higher affinity one. The dissociation constant of the high affinity binding site (androgen response element I) was determined to be approximately 87 nM. The remainder of the enhancer contains elements that function synergistically with the AR. We discuss the structural organization of the PSCA enhancer and compare it with that found in other AR-regulated genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   R1881

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