The Polycystic Kidney Disease-1 Promoter Is a Target of the β-Catenin/T-cell Factor Pathway

Polycystic kidney disease (PKD) results from loss-of-function mutations in the PKD1 gene. There are also reports showing abnormally high levels of PKD1 expression in cystic epithelial cells. At present, nothing is known about the molecular mechanisms regulating the normal expression of thePKD1 gene...

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Veröffentlicht in:The Journal of biological chemistry 2002-08, Vol.277 (33), p.29577-29583
Hauptverfasser: Rodova, Marianna, Islam, M. Rafiq, Maser, Robin L., Calvet, James P.
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container_issue 33
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container_title The Journal of biological chemistry
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creator Rodova, Marianna
Islam, M. Rafiq
Maser, Robin L.
Calvet, James P.
description Polycystic kidney disease (PKD) results from loss-of-function mutations in the PKD1 gene. There are also reports showing abnormally high levels of PKD1 expression in cystic epithelial cells. At present, nothing is known about the molecular mechanisms regulating the normal expression of thePKD1 gene or whether transcriptional disregulation of the PKD1 gene has a role in cyst formation. We have analyzed a 3.3-kb 5′-proximal portion of the human PKD1gene. Sequence analysis revealed the presence of consensus sequences for numerous transactivating factors, including four T-cell factor (TCF) binding elements (TBEs). Transcriptional activity of the 3.3-kb fragment and a series of deletion constructs was assayed in HEK293T cells. A 2.0-kb proximal promoter region containing one of the four TBEs (TBE1) was inducible up to 6-fold by cotransfection with β-catenin. β-catenin-mediated induction was inhibited by dominant-negative TCF and by deletion of the TBE1 sequence. 15- or 109-bp sequences containing the TBE1 site, when cloned upstream of a minimal promoter, were shown to respond to β-catenin induction. Gel shift assays confirmed that the TBE1 site is capable of forming complexes with TCF and β-catenin. To determine whether expression of the endogenous PKD1 gene responds to β-catenin, HT1080 cells were treated with LiCl, and HeLa cells were stably transfected with β-catenin. In both cases, endogenous PKD1 mRNA levels were elevated in response to these treatments. Taken together, these studies define an active PKD1 promoter region and suggest that the PKD1 gene is a target of the β-catenin/TCF pathway.
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source MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Animals
Base Sequence
beta Catenin
Cell Line
Cytoskeletal Proteins - metabolism
DNA Primers
Electrophoretic Mobility Shift Assay
Humans
Promoter Regions, Genetic
Proteins - genetics
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes - metabolism
Trans-Activators - metabolism
TRPP Cation Channels
title The Polycystic Kidney Disease-1 Promoter Is a Target of the β-Catenin/T-cell Factor Pathway
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