Department of Medicine, Banting and Best Diabetes Center, Toronto Hospital, University of Toronto, Ontario, Canada.
The proglucagon gene is expressed in a cell-specific manner in the A cells of the islets and the L cells of the intestine; however, the physiological factors that regulate proglucagon gene expression are not well understood. Although insulin inhibits proglucagon gene transcription in the islets, peptides that stimulate proglucagon gene expression have not been identified. We show here that gastrin-releasing peptide (GRP) induces proglucagon messenger RNA transcripts in STC-1 enteroendocrine cells. The GRP induction of proglucagon gene expression was dose dependent, detectable by 4 h after GRP treatment, and sustained, i.e. detectable after a 24-h GRP incubation. GRP also induced the transcriptional activity of rat proglucagon promoter-luciferase plasmids in transfected STC-1 cells. The GRP induction of proglucagon promoter activity was attenuated, but not eliminated, after deletion of 5'-flanking sequences containing the proglucagon gene cAMP response element (CRE). A mutation in the CRE previously shown to abrogate cAMP responsiveness and CRE-binding protein binding was associated with a reduction in the transcriptional response to GRP. The proglucagon CRE also conferred GRP responsiveness to a truncated proglucagon promoter in STC-1 cells. These observations identify GRP as a peptide activator of proglucagon gene expression and provide evidence linking the proglucagon gene CRE to the physiological control of proglucagon gene expression.