TRANSCRIPTIONAL REGULATION OF THE MOUSE PRESENILIN-1 GENE

The presenilin-1 (PS-1) gene encodes at least three separate mRNA tran scripts from its 12 exons, which are spread over 50 kilobase pairs of mouse DNA. The first transcript begins with exon 1A, whereas the other transcripts begin with exon 1B. Different portions of exon 1B are spl iced to give long and short mRNAs. The expression of all of these tran scripts depends on a single promoter located just upstream of exon 1A. Although this region lacks a TATA box and a number of common initiato r sequences, it does contain a CAAT box, a heat-shock responsive eleme nt, a polyomavirus enhancer activator-3 site, an Ets 1-3 site, and mul tiple-Sp1 and multiple-Ap2 binding sites, which are typically found in eukaryotic promoters. We have combined a reporter gene with various p ortions of this putative PS-1 promoter and measured firefly luciferase activity relative to an internal renilla luciferase standard. We iden tified a 25-base pair fragment spanning the 5'-transcription start sit e of exon 1A as containing the core of the promoter activity. The sequ ences downstream of this region had undetectable promoter activity, su ggesting that this core element is the gene's only promoter, and it co ntrols expression of all three transcripts. Although human PS-1 mRNA e xpression is clearly different from the mouse PS-1 mRNA pattern, the h uman and mouse core promoters do share limited homology.