Regulation of human prostate-specific antigen gene expression in transgenic mice: evidence for an enhancer between the PSA and human glandular kallikrein-1 genes.

The human prostate-specific antigen (PSA) and glandular kallikrein-1 (hGK-1, also known as hK2) genes are tandemly located on chromosome 19, separated by a 12-kb intergenic region. The coordinate regulation of these two genes suggests the presence of common regulatory elements responsible for tissue specificity and/or levels of expression within this region. To identify such regulatory elements, we generated two sets of transgenic mice, which had incorporated either the PSA gene alone or together with the intergenic region. Both sets of transgenics exhibit remarkably prostate-specific expression of the transgene. However, the presence of the intergenic region abrogates the dependence on high PSA gene copy-number for high levels of PSA expression. This suggests the existence of a positive regulatory element in the intergenic region. By using a previously identified distal enhancer element of PSA (termed DEE 1) as a probe, we identified a cross-hybridizing fragment, which we termed DEE 2, in the intergenic region. Sequence analysis shows that DEE 2 is 76% identical to DEE 1, and it includes a putative androgen-responsive element. Here, we propose a model to illustrate how the two enhancers may work to regulate the transcription of PSA and hK2.