Abstract
Claudin-2 is a structural component of tight junctions in the kidneys, liver, and intestine, but the mechanisms regulating its expression have not been defined. The 5'-flanking region of the claudin-2 gene contains binding sites for intestine-specific Cdx homeodomain proteins and hepatocyte nuclear factor (HNF)-1, which are conserved in human and mouse. Both Cdx1 and Cdx2 activated the claudin-2 promoter in the human intestinal epithelial cell line Caco-2. HNF-1alpha augmented the Cdx2-induced but not Cdx1-induced transcriptional activation of the human claudin-2 promoter. In mice, HNF-1alpha was required for claudin-2 expression in the villus epithelium of the ileum and within the liver but not in the kidneys, indicating an organ-specific function of HNF-1alpha in the regulation of claudin-2 gene expression. Tight junction structural components, which determine epithelial polarization and intestinal barrier function, can be regulated by homeodomain proteins that control the differentiation of the intestinal epithelium.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Base Sequence
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Binding Sites
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Blotting, Northern
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Blotting, Western
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CDX2 Transcription Factor
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Caco-2 Cells
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Cell Nucleus / metabolism
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Claudins
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Cloning, Molecular
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DNA Mutational Analysis
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DNA-Binding Proteins*
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Epithelial Cells / metabolism
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Gene Deletion
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Gene Expression Regulation, Neoplastic*
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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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Homeodomain Proteins / metabolism
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Humans
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Ileum / metabolism
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Intestinal Mucosa / metabolism
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Liver / metabolism
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Luciferases / metabolism
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Membrane Proteins / genetics*
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Membrane Proteins / physiology*
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Mice
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Nuclear Proteins*
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Promoter Regions, Genetic*
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Protein Binding
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Protein Structure, Tertiary
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RNA / metabolism
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Tissue Distribution
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Trans-Activators
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Transcription Factors / metabolism*
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Transcriptional Activation
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Transfection
Substances
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CDX1 protein, human
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CDX2 Transcription Factor
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CDX2 protein, human
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CLDN2 protein, human
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Cdx1 protein, mouse
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Claudins
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Cldn2 protein, mouse
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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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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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Hnf1b protein, mouse
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Homeodomain Proteins
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Membrane Proteins
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-beta
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RNA
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Luciferases