TRANSCRIPTIONAL REGULATION OF SECRETIN GENE-EXPRESSION

Expression of the gene encoding the hormone secretin is restricted to a specific enteroendocrine cell type and to p-cells in developing panc reatic islets. To characterize regulatory elements in the secretin gen e responsible for its expression in secretin-producing cells, we used a series of reporter genes for transient expression assays in transfec tion studies carried out in secretin-producing islet cell lines. Analy sis of the transcriptional activity of deletion mutants identified a p ositive cis regulatory domain between 174 and 53 base pairs upstream f rom the transcriptional initiation site which was required for secreti n gene expression in secretin-producing HIT insulinoma cells. Within t his enhancer were sequences resembling two binding sites for the trans cription factor Sp 1, as well as a consensus sequence for binding to h elix-loop-helix proteins. Analysis of these three elements by site-dir ected mutagenesis suggests that each is important for full transcripti onal activity. The role of proximal enhancer sequences in directing se cretin gene expression to appropriate tissues is further supported by studies in transgenic mice revealing that 1.6 kilobases of the secreti n gene 5' flanking sequence were sufficient to direct the expression o f either human growth hormone or simian virus 40 large T-antigen repor ter genes to all major secretin-producing tissues.