A 6-kb Promoter Fragment Mimics in Transgenic Mice the Prostate-Specific and Androgen-Regulated Expression of the Endogenous Prostate-Specific Antigen Gene in Humans

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Abstract
Prostate-specific antigen (PSA) is a kallikrein-like serine protease, which is almost exclusively syn- thesized in the luminal epithelial cells of the human prostate. PSA expression is androgen regulated. Previously, we characterized in vitro the proximal promoter, and a strong enhancer region, approxi- mately 4 kb upstream of the PSA gene. Both re- gions are needed for high, androgen-regulated ac- tivity of the PSA promoter in LNCaP cells. The goal of the present study is the in vivo characterization of the PSA promoter. Three transgenic mouse lines carrying the Escherichia coli LacZ gene, driven by the 632-bp proximal PSA promoter, and three lines with LacZ, driven by the 6-kb PSA promoter, were generated. Expression of the LacZ reporter gene was analyzed in a large series of tissues. Trans- gene expression could not be demonstrated in any of the transgenic animals carrying the proximal PSA promoter. All three lines carrying the 6-kb PSA promoter showed lateral prostate-specific b-ga- lactosidase activity. Transgene expression was un- detectable until 8 weeks after birth. Upon castra- tion, b-galactosidase activity rapidly declined. It could be restored by subsequent androgen admin- istration. A search for mouse PSA-related kallikrein genes expressed in the prostate led to the identi- fication of mGK22, which was previously demon- strated to be expressed in the submandibular sal-

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