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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.

Pubmed ID: 15647252


  • Hiesberger T
  • Shao X
  • Gourley E
  • Reimann A
  • Pontoglio M
  • Igarashi P


The Journal of biological chemistry

Publication Data

March 18, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P50 DK-57328
  • Agency: NIDDK NIH HHS, Id: R01-DK-42921

Mesh Terms

  • Acetyltransferases
  • Animals
  • Binding Sites
  • Butyrates
  • 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
  • Isobutyrates
  • 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