title: Critical role of Egr transcription factors in regulating insulin biosynthesis, blood glucose homeostasis, and islet size.
abstract: Expression of early growth response protein (Egr)-1, a protein of the Egr family of zinc finger transcription factors, is stimulated in glucose-treated pancreatic β-cells and insulinoma cells. The purpose of this study was to elucidate the role of Egr transcription factors in pancreatic β-cells in vivo. To overcome the problem associated with redundancy of functions between Egr proteins, conditional transgenic mice were generated expressing a dominant-negative mutant of Egr-1 in pancreatic β-cells. The Egr-1 mutant interferes with DNA binding of all Egr proteins and thus impairs the biological functions of the entire Egr family. Expression of the Egr-1 mutant reduced expression of TGFβ and basic fibroblast growth factor, known target genes of Egr-1, whereas the expression of Egr-1, Egr-3, Ets-like gene-1 (Elk-1), and specificity protein-3 was not changed in the presence of the Egr-1 mutant. Expression of the homeobox protein pancreas duodenum homeobox-1, a major regulator of insulin biosynthesis, was reduced in islets expressing the Egr-1 mutant. Accordingly, insulin mRNA and protein levels were reduced by 75 or 25%, respectively, whereas expression of glucagon and somatostatin was not altered after expression of the Egr-1 mutant in β-cells. Glucose tolerance tests revealed that transgenic mice expressing the Egr-1 mutant in pancreatic β-cells displayed impaired glucose tolerance. In addition, increased caspase-3/7 activity was detected as a result of transgene expression, leading to a 20% decrease of the size of the islets. These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic β-cells in vivo.
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, Building 44, University of Saarland Medical Center, d-66421 Homburg, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Müller
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Rössler
authors.forename: Christine
authors.initials: C
authors.lastname: Wittig
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D051765:Early Growth Response Transcription Factors / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051381:Rats; D013004:Somatostatin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019076:Transgenes
chemical_list: D001786:Blood Glucose; D051765:Early Growth Response Transcription Factors; D018398:Homeodomain Proteins; D007328:Insulin; D016212:Transforming Growth Factor beta; D013004:Somatostatin; D005934:Glucagon; D005947:Glucose