title: Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-8856, USA. Thomas.Hiesberger@UTSouthwestern.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Hiesberger
authors.forename: Xinli
authors.initials: X
authors.lastname: Shao
authors.forename: Eric
authors.initials: E
authors.lastname: Gourley
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimann
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002087:Butyrates / Q000494:pharmacology; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019281:Dimerization; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D017353:Gene Deletion; D005799:Genes, Dominant; D017930:Genes, Reporter; D006367:HeLa Cells; D051539:Hepatocyte Nuclear Factor 1-beta; D051548:Histone Acetyltransferases; D006801:Humans; D047468:Immunoprecipitation; D058610:Isobutyrates; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D052177:Kidney Diseases, Cystic / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology; D037102:Lectins; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002087:Butyrates; D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; C496496:Hnf1b protein, mouse; D058610:Isobutyrates; D037102:Lectins; C451750:PKHD1 protein, human; C484365:Pkhd1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; C020380:isobutyric acid; D004247:DNA; D000123:Acetyltransferases; D051548:Histone Acetyltransferases