Abstract
Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Child
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Child, Preschool
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Female
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Genes, Reporter
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 1-beta
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Hepatocyte Nuclear Factor 4
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Humans
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Infant
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Islets of Langerhans / physiology*
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Male
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Pedigree
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Promoter Regions, Genetic
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Transcription, Genetic*
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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HNF1A protein, human
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HNF1B protein, human
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HNF4A protein, human
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 4
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MLX protein, human
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Nuclear Proteins
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Phosphoproteins
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Receptors, Glucocorticoid
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Tcfl4 protein, mouse
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Transcription Factors
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-beta