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J. Biol. Chem., Vol. 277, Issue 33, 29577-29583, August 16, 2002
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From the Department of Biochemistry and Molecular Biology and the
Kidney Institute, University of Kansas Medical Center, Kansas City,
Kansas 66160 and the 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 the
PKD1 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 PKD1
gene. 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
The Polycystic Kidney Disease-1 Promoter Is a Target of the
-Catenin/T-cell Factor Pathway*
, Department of
Chemistry/Physics, Northwest Missouri State University,
Maryville, Missouri 64468
-catenin. -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 -catenin induction. Gel
shift assays confirmed that the TBE1 site is capable of forming complexes with TCF and -catenin. To determine whether expression of
the endogenous PKD1 gene responds to -catenin, HT1080
cells were treated with LiCl, and HeLa cells were stably transfected with -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 -catenin/TCF pathway.
*
This work was supported by National Institutes of Health
Grants P50 DK57301 (to J. P. C. and R. L. M.) and P01 DK53763 (to J. P. C.) and by grants from the Polycystic Kidney Disease Foundation and the University of Kansas Medical Center Research Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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