Prostate-specific antigen: gene structure and regulation of expression

As a start of our study of prostate-specific and androgen-dependent expression of PA, various PA cDNAs (Chapter II) and the PA gene (Chapter Ill) were isolated and characterized. The PA gene turned out to be a member of a small kaHikrein family, encompassing two other closely related genes Ithe human Glandular Kal!ikrein-1 gene (hGK-1), and the tissue kallikrein gene {KLK1)]. Genetic characterization of the human kallikrein genes showed clustering in a 60 kb segment on chromosome 19q13.2-13.4 (Chapters IV and V). The hGK-1 gene shows a strong homology to PA and is, similarly to PA, exclusively expressed in prostate tissue. KLK1 is mainly expressed in kidney, pancreas and salivary glands. In addition to PA eDNA, hGK-1 cDNAs were isolated and characterized. This allowed the comparison of PA and hGK-1 mRNA expression. Using hGK-1 and ?A-specific eDNA probes, androgen-stimulated mRNA expression of PA and hGK-1 could be determined (Chapter VI). Further, an androgen responsive element in the promoter region of the PA gene was defined and tested for its functional activity (Chapter Vl!). The homology of the PA, hGK-1 and KLK1 genes does not only include the open reading frame, but extends into the promoter regions, although the genes are at least partially expressed in different tissues and at different levels. The above mentioned aspects, resulted in the development of a model system for the study of tissue-specific and hormone-responsive gene expression in the human prostate.