6.4. Conclusion

This study focused on the promoter activities and hormonal regulation of the hPAP gene in transient transfections of cell lines, as well as the promoter activities in transgenic mice models. Androgen regulates the hPAP gene differently in LNCaP cells than it does the other prostate-related genes hPSA and hK2; androgens could not directly regulate hPAP expression via receptor binding to AREs located at -178 of the proximal promoter or at +336 of the first intron of the gene. The promoter and first intron fragment -734/+467 of the hPAP gene could direct and also restrict the gene expression mainly in prostate epithelium. A prostatic regulatory protein could bind to multiple binding sites with the GAAAATATGATA or homologous sequence along the promoter and the first intron of the hPAP gene with different affinities, and hence could be involved in the regulation of the prostate-specific expression of the hPAP gene in a bidirectional manner, depending on the hormone status.

The hPAP gene is a good model in studying hormone regulation and tissue/cell-specific regulation of gene expression, although the real physiological role of hPAP is not yet clear. Since no mutation of the hPAP gene has been found in clinics so far, the generation of PAP gene-deficient knock-out mice becomes very important in demonstrating the exact function of PAP, and may also be helpful to clarify the hormonal regulation and prostate-specific regulation of the gene. Study of the hPAP promoter may have a significant medical impact. The further understanding of the molecular mechanisms behind the androgen regulation and prostate-specific regulation of hPAP promoter might lead to the improvement of the clinical practice for prostate cancer by using therapeutic genes under the tight control of a highly active and prostate-specific promoter.