PROSTATE-SPECIFIC ANTIGEN EXPRESSION IS REGULATED BY AN UPSTREAM ENHANCER

Prostate cancer can be detected using assays for blood-borne prostate- specific antigen (PSA), which is the clinically most useful diagnostic marker of malignant disease, This paper characterizes the 5'-flanking prostate-specific enhancer which controls expression of the human PSA gene This enhancer, located between -5824 and -3738, is androgen-resp onsive and requires a promoter for activity, Inductions of 12-100-fold activity occur at 1 nM concentrations of the testosterone analog R188 1. The enhancer demonstrated tissue specificity as judged by transfect ions of several human cell lines. Electrophoretic mobility shift assay s comparing nuclear extracts from breast cancer cells MCF-7, and prost ate cancer cells LNCaP, showed three regions of prostate-specific bind ing, These three regions are -4168 to -4797 (region I), -4710 to 4479 (region II), and -4168 to -3801 (region III), Region III contained a p utative androgen response element at -4136 that markedly affected acti vity if mutated, These data suggest that prostate-specific gene expres sion may involve interaction of prostate-specific proteins or protein complexes with the enhancer in addition to binding of the androgen rec eptor to androgen response elements.