The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription
Open Access
- 5 March 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 37 (8), 2529-2538
- https://doi.org/10.1093/nar/gkp122
Abstract
Glis3 is a member of the Krüppel-like family of transcription factors and is highly expressed in islet β cells. Mutations in GLIS3 cause the syndrome of neonatal diabetes and congenital hypothyroidism (NDH). Our aim was to examine the role of Glis3 in β cells, specifically with regard to regulation of insulin gene transcription. We demonstrate that insulin 2 (Ins2) mRNA expression in rat insulinoma 832/13 cells is markedly increased by wild-type Glis3 overexpression, but not by the NDH1 mutant. Furthermore, expression of both Ins1 and Ins2 mRNA is downregulated when Glis3 is knocked down by siRNA. Glis3 binds to the Ins2 promoter in the cell, detected by chromatin immunoprecipitation. Deletion analysis of Ins2 promoter identifies a sequence (5′-GTCCCCTGCTGTGAA-3′) from −255 to −241 as the Glis3 response element and binding occur specifically via the Glis3 zinc finger region as revealed by mobility shift assays. Moreover, Glis3 physically and functionally interacts with Pdx1, MafA and NeuroD1 to modulate Ins2 promoter activity. Glis3 also may indirectly affect insulin promoter activity through upregulation of MafA and downregulation of Nkx6-1. This study uncovers a role of Glis3 for regulation of insulin gene expression and expands our understanding of its role in the β cell.Keywords
This publication has 35 references indexed in Scilit:
- Glucose-Mediated Transactivation of Carbohydrate Response Element-Binding Protein Requires Cooperative Actions from Mondo Conserved Regions and EssentialTrans-Acting Factor 14-3-3Molecular Endocrinology, 2008
- Krüppel-Like Zinc Finger Protein Glis2 Is Essential for the Maintenance of Normal Renal FunctionsMolecular and Cellular Biology, 2008
- Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1)Nucleic Acids Research, 2008
- Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and SecretionMolecular and Cellular Biology, 2007
- Krüppel-Like Zinc Finger Protein Glis3 Promotes Osteoblast Differentiation by Regulating FGF18 ExpressionJournal of Bone and Mineral Research, 2007
- MafB is required for islet β cell maturationProceedings of the National Academy of Sciences of the United States of America, 2007
- Comparative Analysis of Insulin Gene PromotersDiabetes, 2006
- Identification of Glis1, a Novel Gli-related, Krüppel-like Zinc Finger Protein Containing Transactivation and Repressor FunctionsPublished by Elsevier BV ,2002
- β-Cell Differentiation Factor Nkx6.1 Contains Distinct DNA Binding Interference and Transcriptional Repression DomainsPublished by Elsevier BV ,2000
- A Silencer and an Adjacent Positive Element Interact to Modulate the Activity of the Human Insulin PromoterEuropean Journal of Biochemistry, 1995