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Scientific article
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English

Bone morphogenetic protein 3 controls insulin gene expression and is down-regulated in INS-1 cells inducibly expressing a hepatocyte nuclear factor 1A-maturity-onset diabetes of the young mutation

Published inThe Journal of biological chemistry, vol. 286, no. 29, p. 25719-25728
Publication date2011
Abstract

Inactivating mutations in the transcription factor hepatocyte nuclear factor (HNF) 1A cause HNF1A-maturity-onset diabetes of the young (HNF1A-MODY), the most common monogenic form of diabetes. To examine HNF1A-MODY-induced defects in gene expression, we performed a microarray analysis of the transcriptome of rat INS-1 cells inducibly expressing the common hot spot HNF1A frameshift mutation, Pro291fsinsC-HNF1A. Real-time quantitative PCR (qPCR), Western blotting, immunohistochemistry, reporter assays, and chromatin immunoprecipitation (ChIP) were used to validate alterations in gene expression and to explore biological activities of target genes. Twenty-four hours after induction of the mutant HNF1A protein, we identified a prominent down-regulation of the bone morphogenetic protein 3 gene (Bmp-3) mRNA expression. Reporter assays, qPCR, and Western blot analysis validated these results. In contrast, inducible expression of wild-type HNF1A led to a time-dependent increase in Bmp-3 mRNA and protein levels. Moreover, reduced protein levels of BMP-3 and insulin were detected in islets of transgenic HNF1A-MODY mice. Interestingly, treatment of naïve INS-1 cells or murine organotypic islet cultures with recombinant human BMP-3 potently increased their insulin levels and restored the decrease in SMAD2 phosphorylation and insulin gene expression induced by the HNF1A frameshift mutation. Our study suggests a critical link between HNF1A-MODY-induced alterations in Bmp-3 expression and insulin gene levels in INS-1 cells and indicates that the reduced expression of growth factors involved in tissue differentiation may play an important role in the pathophysiology of HNF1A-MODY.

Keywords
  • Animals
  • Bone Morphogenetic Protein 3/pharmacology
  • Cell Line, Tumor
  • Down-Regulation/drug effects/genetics
  • Frameshift Mutation/drug effects
  • Gene Expression Profiling
  • Hepatocyte Nuclear Factor 1-alpha/genetics
  • Humans
  • Insulin/genetics
  • Insulin-Secreting Cells/drug effects/metabolism
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic/genetics
  • Rats
Citation (ISO format)
BONNER, Caroline et al. Bone morphogenetic protein 3 controls insulin gene expression and is down-regulated in INS-1 cells inducibly expressing a hepatocyte nuclear factor 1A-maturity-onset diabetes of the young mutation. In: The Journal of biological chemistry, 2011, vol. 286, n° 29, p. 25719–25728. doi: 10.1074/jbc.M110.215525
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Article (Published version)
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Identifiers
ISSN of the journal0021-9258
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