|
rdf:type |
|
|
lifeskim:mentions |
umls-concept:C0022646,
umls-concept:C0035820,
umls-concept:C0040649,
umls-concept:C0085548,
umls-concept:C0126037,
umls-concept:C1418605,
umls-concept:C1514562,
umls-concept:C1707271,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221
|
|
pubmed:issue |
11
|
|
pubmed:dateCreated |
2005-3-14
|
|
pubmed:abstractText |
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:grant |
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acetyltransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Butyric Acids,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/HNF1B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 1-beta,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Acetyltransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Hnf1b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Isobutyric Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Lectins,
http://linkedlifedata.com/resource/pubmed/chemical/PKHD1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Pkhd1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/isobutyric acid
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Mar
|
|
pubmed:issn |
0021-9258
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
18
|
|
pubmed:volume |
280
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
10578-86
|
|
pubmed:dateRevised |
2010-11-18
|
|
pubmed:meshHeading |
pubmed-meshheading:15647252-Acetyltransferases,
pubmed-meshheading:15647252-Animals,
pubmed-meshheading:15647252-Binding Sites,
pubmed-meshheading:15647252-Butyric Acids,
pubmed-meshheading:15647252-Cell Proliferation,
pubmed-meshheading:15647252-DNA,
pubmed-meshheading:15647252-DNA-Binding Proteins,
pubmed-meshheading:15647252-Dimerization,
pubmed-meshheading:15647252-Down-Regulation,
pubmed-meshheading:15647252-Epithelial Cells,
pubmed-meshheading:15647252-Gene Deletion,
pubmed-meshheading:15647252-Genes, Dominant,
pubmed-meshheading:15647252-Genes, Reporter,
pubmed-meshheading:15647252-HeLa Cells,
pubmed-meshheading:15647252-Hepatocyte Nuclear Factor 1-beta,
pubmed-meshheading:15647252-Histone Acetyltransferases,
pubmed-meshheading:15647252-Humans,
pubmed-meshheading:15647252-Immunoprecipitation,
pubmed-meshheading:15647252-Isobutyric Acids,
pubmed-meshheading:15647252-Kidney,
pubmed-meshheading:15647252-Kidney Diseases, Cystic,
pubmed-meshheading:15647252-Kidney Tubules,
pubmed-meshheading:15647252-Lectins,
pubmed-meshheading:15647252-Mice,
pubmed-meshheading:15647252-Mice, Transgenic,
pubmed-meshheading:15647252-Microscopy, Fluorescence,
pubmed-meshheading:15647252-Mutation,
pubmed-meshheading:15647252-Plasmids,
pubmed-meshheading:15647252-Promoter Regions, Genetic,
pubmed-meshheading:15647252-Protein Binding,
pubmed-meshheading:15647252-Protein Structure, Tertiary,
pubmed-meshheading:15647252-RNA, Messenger,
pubmed-meshheading:15647252-Receptors, Cell Surface,
pubmed-meshheading:15647252-Transcription, Genetic,
pubmed-meshheading:15647252-Transcription Factors,
pubmed-meshheading:15647252-Transfection
|
|
pubmed:year |
2005
|
|
pubmed:articleTitle |
Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis.
|
|
pubmed:affiliation |
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-8856, USA. Thomas.Hiesberger@UTSouthwestern.edu
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|
