The glucagon gene is expressed in the endocrine pancreas, the intestine, and the brain. In the endocrine pancreas, expression of the glucagon gene is restricted to the alpha cells of the islets of Langerhans. We previously showed that 168 base pairs of the promoter was critical for this restricted expression. To further characterize the mechanisms involved in alpha cell specificity, we analyzed the responsible DNA sequences by transient transfection studies into glucagon- and insulin-producing cell lines. We localized alpha cell-specific sequences between nt 100 and 52, a region that corresponds to the upstream promoter element 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, bind on closely overlapping sequences, display similar methylation interference patterns, and appear to be related complexes. Point mutations of G1 indicate, however, that their binding specificities are different. All four complexes are islet-specific, and impairment of their binding results in decreased transcription. We conclude that G1 interacts with islet cell-specific proteins to restrict glucagon gene expression to the alpha cells.

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