The zinc finger-containing transcription factor Gata-4 is expressed in the developing endocrine pancreas and activates glucagon gene expression

Article Article scientifique Article The zinc finger-containing transcription factor Gata-4 is expressed in the developing endocrine pancreas and activates glucagon gene expression eng 2005 author Ritz-Laser Beate author Mamin Aline 133667 author Brun Thierry 0000-0002-1659-4283 24644 author Avril Isabelle 559481 author Schwitzgebel Luscher Valérie 133261 author Philippe Jacques 26481 759-770 10.1210/me.2004-0051 15539431 0888-8809 Gene inactivation studies have shown that members of the Gata family of transcription factors are critical for endoderm development throughout evolution. We show here that Gata-4 and/or Gata-6 are not only expressed in the adult exocrine pancreas but also in glucagonoma and insulinoma cell lines, whereas Gata-5 is restricted to the exocrine pancreas. During pancreas development, Gata-4 is expressed already at embryonic d 10.5 and colocalizes with early glucagon+ cells at embryonic d 12.5. Gata-4 was able to transactivate the glucagon gene both in heterologous BHK-21 (nonislet Syrian baby hamster kidney) and in glucagon-producing InR1G9 cells. Using gel-mobility shift assays, we identified a complex formed with nuclear extracts from InR1G9 cells on the G5 control element (-140 to -169) of the glucagon gene promoter as Gata-4. Mutation of the GATA binding site on G5 abrogated the transcriptional activation mediated by Gata-4 and reduced basal glucagon gene promoter activity in glucagon-producing cells by 55%. Furthermore, Gata-4 acted more than additively with Forkhead box A (hepatic nuclear factor-3) to trans-activate the glucagon gene promoter. We conclude that, besides its role in endoderm differentiation, Gata-4 might be implicated in the regulation of glucagon gene expression in the fetal pancreas and that Gata activity itself may be modulated by interactions with different cofactors. Animals Base Sequence Binding Sites Cell Differentiation Cell Line Cell Nucleus/metabolism Chloramphenicol O-Acetyltransferase/metabolism Cricetinae DNA-Binding Proteins/chemistry/metabolism Dose-Response Relationship, Drug GATA4 Transcription Factor GATA6 Transcription Factor Gene Expression Regulation Glucagon/metabolism Humans Islets of Langerhans/metabolism Mice Microscopy, Fluorescence Molecular Sequence Data Mutation Pancreas/embryology Promoter Regions, Genetic Protein Binding Reverse Transcriptase Polymerase Chain Reaction Time Factors Tissue Distribution Transcription Factors/chemistry/metabolism Transcriptional Activation Transfection Zinc Fingers Dewey 612 Dewey 616 Dewey 618 134 Département de physiologie cellulaire et métabolisme 21C 56 Département de médecine 221 58 Département de pédiatrie, gynécologie et obstétrique 223 false 144 Diabète et métabolisme 178 23 Diabète et régulation des gènes 36 Molecular endocrinology 19 3 1a951a03-a42f-4287-b2a7-26014dc480ec Article (Published version) Restricted 759-770.pdf 451099 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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