Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis.
Hepatocyte nuclear factor-1beta (HNF-1beta) is a homeodomain-containing transcription factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1beta produce congenital cystic abnormalities of the kidney, and previous studies showed that HNF-1beta regulates the expression of the autosomal recessive polycystic kidney disease (ARPKD) gene, Pkhd1. ... Here we show that the C-terminal region of HNF-1beta contains an activation domain that is functional when fused to a heterologous DNA-binding domain. An HNF-1beta deletion mutant lacking the C-terminal domain interacts with wild-type HNF-1beta, binds DNA, and functions as a dominant-negative inhibitor of a chromosomally integrated Pkhd1 promoter. The activation of the Pkhd1 promoter by wild-type HNF-1beta is stimulated by sodium butyrate or coactivators CREB (cAMP-response element)-binding protein (CBP) and P/CAF. The interaction with CBP and P/CAF requires the C-terminal domain. Expression of an HNF-1beta C-terminal deletion mutant in transgenic mice produces renal cysts, increased cell proliferation, and dilatation of the ureter similar to mice with kidney-specific inactivation of HNF-1beta. Pkhd1 expression is inhibited in cystic collecting ducts but not in non-cystic proximal tubules, despite transgene expression in this nephron segment. We conclude that the C-terminal domain of HNF-1beta is required for the activation of the Pkhd1 promoter. Deletion mutants lacking the C-terminal domain function as dominant-negative mutants, possibly by preventing the recruitment of histone acetylases to the promoter. Cyst formation correlates with inhibition of Pkhd1 expression, which argues that mutations of HNF-1beta produce kidney cysts by down-regulating the ARPKD gene, Pkhd1. Expression of HNF-1alpha in proximal tubules may protect against cystogenesis.
Mesh Terms:
Acetyltransferases, Animals, Binding Sites, Butyric Acids, Cell Proliferation, DNA, DNA-Binding Proteins, Dimerization, Down-Regulation, Epithelial Cells, Gene Deletion, Genes, Dominant, Genes, Reporter, Hela Cells, Hepatocyte Nuclear Factor 1-beta, Histone Acetyltransferases, Humans, Immunoprecipitation, Isobutyric Acids, Kidney, Kidney Diseases, Cystic, Kidney Tubules, Lectins, Mice, Mice, Transgenic, Microscopy, Fluorescence, Mutation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Messenger, Receptors, Cell Surface, Transcription Factors, Transcription, Genetic, Transfection
Acetyltransferases, Animals, Binding Sites, Butyric Acids, Cell Proliferation, DNA, DNA-Binding Proteins, Dimerization, Down-Regulation, Epithelial Cells, Gene Deletion, Genes, Dominant, Genes, Reporter, Hela Cells, Hepatocyte Nuclear Factor 1-beta, Histone Acetyltransferases, Humans, Immunoprecipitation, Isobutyric Acids, Kidney, Kidney Diseases, Cystic, Kidney Tubules, Lectins, Mice, Mice, Transgenic, Microscopy, Fluorescence, Mutation, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Messenger, Receptors, Cell Surface, Transcription Factors, Transcription, Genetic, Transfection
J. Biol. Chem.
Date: Mar. 18, 2005
PubMed ID: 15647252
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