Glucagon gene expression is negatively regulated by insulin at the transcriptional level. G3, a DNA control element located in the 5`-flanking sequence of the rat glucagon gene mediates the inhibition of transcription, which occurs in response to insulin. We show here that two islet-specific protein complexes C1A and C1B, bind to the A domain of G3, which is critical for the insulin response. These two complexes bind to overlapping sequences of the A domain and display very similar binding specificities. Point mutations in the A domain that affect binding of C1A and C1B result in both decreased G3 enhancer activity and insulin-mediated inhibitory effects with a close correlation between diminution of binding and function. One of the two complexes, C1A, is similar or identical to B1, a protein complex interacting with the upstream promoter element of the glucagon gene, G, implicated in the A cell-specific expression of the glucagon gene. Our data indicate that islet-specific proteins are involved in glucagon gene regulation by insulin.

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