DIFFERENTIAL REGULATION OF THE GLUCAGON AND INSULIN-I GENE PROMOTERS BY THE BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS E47 AND BETA2

The insulin and glucagon genes are expressed in the beta and alpha cel ls of the islets of Langerhans, respectively, The factors controlling their cell- and islet-specific expression are poorly known. Insulin-en hancer factor-1 (IEF1) has previously been shown to interact with the E boxes of the rat insulin I and II genes and was proposed to play a c ritical role in beta cell-specific expression. BETA2, a recently ident ified basic helix-loop-helix (bHLH) protein, binds with high affinity and transactivates the rat insulin II gene upon dimerization with the ubiquitous bHLH protein E47, We show here that the heterodimer E47/BET A2 also binds and transactivates the rat insulin I and glucagon genes and exhibits the same characteristics as IEF1. In transfection experim ents, the E boxes of the insulin I and glucagon genes confer transcrip tional activity in both insulin- and glucagon-producing cells, which i s increased by overexpression of E47 and BETA2, However, overexpressio n of E47 inhibits only E box-mediated glucagon gene expression, wherea s it activates insulin gene transcription, indicating that the E boxes of the insulin and glucagon genes display gene-specific characteristi cs. We conclude that the heterodimer E47/BETA2 represents an islet-spe cific factor that controls both insulin and glucagon gene transcriptio n and that the E47/BETA2 ratio may be important for regulated gene exp ression.