THE UPSTREAM PROMOTER ELEMENT OF THE GLUCAGON GENE, G1, CONFERS PANCREATIC ALPHA CELL-SPECIFIC EXPRESSION

The glucagon gene is expressed in the endocrine pancreas, the intestin e, and the brain. In the endocrine pancreas, expression of the glucago n gene is restricted to the alpha cells of the islets of Langerhans. W e previously showed that 168 base pairs of the promoter was critical f or this restricted expression. To further characterize the mechanisms involved in alpha cell specificity, we analyzed the responsible DNA se quences by transient transfection studies into glucagon- and insulin-p roducing cell Lines. We localized alpha cell-specific sequences betwee n nt 100 and 52, a region that corresponds to the upstream promoter el ement G1. Four protein complexes, B1, B2, B3, and B6 interact with G1; B6 requires most of G1 to be formed. B1, B2, and B3, by contrast, bin d on closely overlapping sequences, display similar methylation interf erence patterns, and appear to be related complexes. Point mutations o f G1 indicate, however, that their binding specificities are different . All four complexes are islet-specific, and impairment of their bindi ng results in decreased transcription. We conclude that G1 interacts w ith islet cell-specific proteins to restrict glucagon gene expression to the alpha cells.