A tissue-specific enhancer of the prostate-specific membrane antigen gene,FOLH1

Prostate-specific membrane antigen (PSMA) is an integral membrane protein t hat is highly expressed on the surface of prostate epithelial cells. It is also expressed on the vascular endothelium of a number of tumor types. We h ave used an enhancer trap approach with randomly cleaved overlapping DNA fr agments from an approximately 55-kb P1 cosmid insert encompassing the 5' ha lf and upstream sequences of the PSMA gene (FOLH1) to isolate an enhancer t hat strongly activates the FOLH1 core promoter region. The enhancer (PSME) is located in the third intron about 12 kb downstream from the start site o f transcription and is characterized by a 72-bp direct repeat within a 331- bp core region. The PSME activates transcription from its own and heterolog ous promoters in prostate cell lines; enhancement is greatest in the PSMA-e xpressing cell line LNCaP (>250-fold). The PSME shows essentially no activi ty in five nonprostate cell lines. PSME-enhanced expression is repressed in the presence of androgen, mimicking the repression of the endogenous FOLH1 gene. The data demonstrate that both cell-type specificity and androgen re gulation are intrinsic properties of the enhancer. These properties make th e PSME an excellent candidate for regulation of gene expression in gene the rapy approaches to prostate cancer, (C) 2001 Academic Press.