A TRANSGENIC STRATEGY FOR ANALYZING THE REGULATORY REGIONS OF THE HUMAN PROSTATE-SPECIFIC ANTIGEN GENE - POTENTIAL APPLICATIONS FOR THE TREATMENT OF PROSTATE-CANCER (REVIEW)

Prostate-specific antigen (PSA) has been used clinically as a marker f or the diagnosis and staging of prostate cancer due to its specific ex pression in prostate epithelial cells. In addition to its medical impo rtance, its complex hormonal and tissue-specific regulation makes it a n attractive model to study gene regulation. Two approaches have been applied to the identification of regulatory regions which confer this specific expression pattern. In vitro analysis of the regulatory regio ns of the human PSA gene using promoter reporter constructs and tumor cell lines has revealed a number of the DNA sequences involved in the hormone-dependent expression of PSA. We have pursued an alternative in vivo approach using transgenic animal technology, which is the focus of this review. Using this second approach, a transgenic mouse was gen erated using a 14 kilobase (kb) region of the human PSA gene encompass ing the coding region and intervening sequences as well as 6 kb of ups tream sequence and 2 kb of downstream sequence. This genomic DNA clone confers a PSA expression pattern in mice which appears to be very sim ilar if not identical to that of humans, allowing us to investigate ti ssue-specificity and developmental regulation of PSA expression. In ad dition, these mice, for which PSA is a self-antigen, provide a model t o test the feasibility and efficacy of PSA-directed immunotherapy for prostate cancer. The further identification of the PSA regulatory regi ons important for tissue-specificity may ultimately allow the design o f new therapeutics for the treatment of prostate cancer.