Abstract
The winged helix transcription factors HNF-3/FKH (forkhead homologs) activate endodermal-derived and acute-phase gene expression and control gut development in Drosophila. Trefoil factor family (TFFs) peptides are vertebrate products secreted by mucin-producing epithelial cells of the gastrointestinal tract involved in restitution and repair of the mucosa. They are positively regulated in ulcerative and neoplastic conditions. We describe a consensus sequence in human and rodent TFF promoters close to the TATAA box showing striking similarity to the binding site of the HNF-3/FKH family. In gel retardation assays, HNF-3 alpha and beta bound predominantly to the site in TFF1 (formerly pS2) and, to a lesser extent, to the sites in TFF2 or TFF3. Mutations generated in this motif severely impaired transcription of TFF1 reporter genes. Cotransfection with expression vectors of HNF-3alpha and beta, but not the related HFH 11A and B, specifically activated the wild-type TFF1 reporter genes. Activation of endogenous expression of TFF1 by HNF-3 alpha and beta gene products was more than 1000 fold in the pancreatic cell line Capan-2 and fivefold in the gastric cell line MKN-45, whereas the intestinal cell lines HUTU 80 and HT-29 displayed no effect. Thus, HNF-3/FKH factors contribute causally to cell-specific regulation of TFF genes and may explain the acute-phase response of TFF peptides.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Cell Nucleus / chemistry
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Cell Nucleus / metabolism
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Cell-Free System / chemistry
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Cell-Free System / metabolism
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DNA-Binding Proteins / genetics
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Forkhead Box Protein M1
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Forkhead Transcription Factors
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Gene Expression Regulation, Neoplastic
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Genes, Reporter / genetics
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Growth Substances / genetics*
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Growth Substances / metabolism
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Hepatocyte Nuclear Factor 3-alpha
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Hepatocyte Nuclear Factor 3-beta
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Humans
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Molecular Sequence Data
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Mucins*
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Muscle Proteins*
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Mutagenesis
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Neuropeptides*
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Nuclear Proteins / genetics
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Peptides / genetics*
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Peptides / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Proteins / genetics*
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Proteins / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Nucleic Acid
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TATA Box
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Trefoil Factor-1
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Trefoil Factor-2
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Trefoil Factor-3
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Tumor Cells, Cultured / chemistry
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Proteins
Substances
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DNA-Binding Proteins
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FOXA1 protein, human
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FOXA2 protein, human
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FOXI1 protein, human
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FOXJ1 protein, human
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FOXM1 protein, human
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Forkhead Box Protein M1
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Forkhead Transcription Factors
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Foxm1 protein, rat
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Growth Substances
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Hepatocyte Nuclear Factor 3-alpha
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Mucins
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Muscle Proteins
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Neuropeptides
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Nuclear Proteins
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Peptides
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Proteins
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Recombinant Fusion Proteins
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TFF1 protein, human
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TFF2 protein, human
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TFF3 protein, rat
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Tff2 protein, rat
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Trans-Activators
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Transcription Factors
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Trefoil Factor-1
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Trefoil Factor-2
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Trefoil Factor-3
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Tumor Suppressor Proteins
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Hepatocyte Nuclear Factor 3-beta