Abstract
Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1alphaand HNF-4alpha genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression by HNF-3alpha and HNF-3beta was studied in embryoid bodies in which one or both HNF-3alpha or HNF-3beta alleles were inactivated. HNF-3beta positively regulated the expression of HNF-4alpha/HNF-1alpha and their downstream targets, implicating a role in diabetes. HNF-3beta was also necessary for expression of HNF-3alpha. In contrast, HNF-3alpha acts as a negative regulator of HNF-4alpha/HNF-1alpha demonstrating that HNF-3alpha and HNF-3beta have antagonistic transcriptional regulatory functions in vivo. HNF-3alpha does not appear to act as a classic biochemical repressor but rather exerts its negative effect by competing for HNF-3 binding sites with the more efficient activator HNF-3beta. In addition, the HNF-3alpha/HNF-3beta ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Cell Differentiation
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Clone Cells
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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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Embryonic and Fetal Development
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Endoderm / cytology
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Endoderm / metabolism*
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Gene Expression Regulation*
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Gene Expression Regulation, Developmental*
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Gene Targeting
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Glucose / metabolism
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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 3-alpha
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Hepatocyte Nuclear Factor 3-beta
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Hepatocyte Nuclear Factor 4
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Insulin / pharmacology
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Mice
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phenotype
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Phosphoproteins / genetics
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Stem Cells
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Up-Regulation
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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Foxa1 protein, mouse
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Foxa2 protein, mouse
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 3-alpha
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Hepatocyte Nuclear Factor 4
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Hnf1a protein, mouse
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Hnf1b protein, mouse
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Insulin
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Nuclear Proteins
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Phosphoproteins
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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 3-beta
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Hepatocyte Nuclear Factor 1-beta
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Glucose