Structure, evolution and expression of glandular kallikrein genes

Abstract: Prostate-specific antigen (PSA) is a worldwide used tool for the diagnosis and monitoring of prostate cancer. It is a serine protease and belongs to the family of glandular kallikreins. Humans have three classical glandular kallikreins, but it has been reported that rodents have many more. Lately, the family has been expanded to contain 12 new genes, KLK4–KLK15, that are situated at the same locus on 19q13.3–13.4 in humans. In our phylogenetic analysis, we were able to demonstrate that the classical glandular kallikrein genes can be considered a subgroup of the expanded glandular kallikrein family. The tissue kallikrein gene has 14 functional paralogs in the mouse and 10 in the rat, but there is only a single copy in artiodactyls, dogs and primates. The arginine esterase in the canine prostate is the only identified functional ortholog of the progenitor to human PSA and hK2. In contrast, KLK4–KLK15 are conserved in the mouse and rat, suggesting that they can be used as model systems to elucidate the physiological importance of these genes. We found that AREIII in the distal promoter region of KLK2 related genes contained deletions in all pseudogenes, whereas it is intact in all functional genes investigated in the present study, which implies that such deletions may represent a step in the process leading to the silencing of KLK2 genes. Repair of the AREIII in the cotton-top tamarin KLK2H2 pseudogene, led to restoration of full transcriptional activity, confirming the importance of this element. Both PSA and hK2 were found to be expressed in many non-prostatic tissues, but at much lower levels than in the prostate. Furthermore, it was shown that PSA in ileum exhibits comparable proteolytic activity and potential to form complexes with protease inhibitors as does PSA in prostate.