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 cells of the islets of Langerhans, respectively. The factors controlling their cell- and islet-specific expression are poorly known. Insulin-enhancer 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 critical role in beta cell-specific expression. BETA2, a recently identified 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/BETA2 also binds and transactivates the rat insulin I and glucagon genes and exhibits the same characteristics as IEF1. In transfection experiments, the E boxes of the insulin I and glucagon genes confer transcriptional activity in both insulin- and glucagon-producing cells, which is increased by overexpression of E47 and BETA2. However, overexpression of E47 inhibits only E box-mediated glucagon gene expression, whereas it activates insulin gene transcription, indicating that the E boxes of the insulin and glucagon genes display gene-specific characteristics. We conclude that the heterodimer E47/BETA2 represents an islet-specific factor that controls both insulin and glucagon gene transcription and that the E47/BETA2 ratio may be important for regulated gene expression.
Unité de Diabétologie Clinique, Centre Médical Universitaire, CH-1211 Genève 4, Switzerland.
E
E
Dumonteil
B
B
Laser
I
I
Constant
J
J
Philippe
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D019281:Dimerization; D005786:Gene Expression Regulation / Q000235:genetics; D005934:Glucagon / Q000235:genetics*; D018257:Helix-Loop-Helix Motifs / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000502:physiology; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000032:analysis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics*; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005934:Glucagon; D018398:Homeodomain Proteins; D007328:Insulin; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C064943:IEBP1 protein, rat; C553060:Tcf7l1 protein, rat; C063843:insulin gene enhancer binding protein Isl-1