RGD Reference Report - Polycystic kidneys caused by sustained expression of Cux1 isoform p75. - Rat Genome Database

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Polycystic kidneys caused by sustained expression of Cux1 isoform p75.

Authors: Cadieux, C  Harada, R  Paquet, M  Cote, O  Trudel, M  Nepveu, A  Bouchard, M 
Citation: Cadieux C, etal., J Biol Chem. 2008 May 16;283(20):13817-24. doi: 10.1074/jbc.M709332200. Epub 2008 Mar 20.
RGD ID: 7207457
Pubmed: PMID:18356167   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M709332200   (Journal Full-text)

The transcriptional regulator Cux1 (CDP, Cutl1) is aberrantly expressed in mouse models for polycystic kidney disease. Here we show that p75-Cux1, the shortest isoform of Cux1, transcribed from an alternative promoter within intron 20, is also deregulated in polycystic kidneys derived from Pkd1 mutant embryos. To determine the role of the p75-Cux1 isoform in cystogenesis, we generated transgenic mice expressing p75-CUX1 in the kidneys and other tissues. Strikingly, these animals developed polycystic kidneys at variable penetrance and severity, correlating with transgene expression levels. Histological and marker analysis of p75-CUX1-derived polycystic kidneys revealed renal cysts derived from the tubular nephron, supporting a model of autosomal dominant polycystic kidney disease. Transgenic p75-CUX1 kidneys additionally showed an up-regulation of the protooncogene c-myc and a down-regulation of the cyclin-dependent kinase inhibitor p27. Chromatin affinity purification experiments confirmed the direct interaction of Cux1 with the c-myc and p27 promoters. These molecular alterations were accompanied by an increase in cilia length and in the proliferative index of epithelial cells lining the cysts. Together, these results identify an important role for the short isoform of CUX1 in polycystic kidney disease development.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
autosomal dominant polycystic kidney disease  ISOMyc (Mus musculus)7207457; 7207457mRNA:increased expression:kidney (mouse)RGD 
autosomal dominant polycystic kidney disease  IEP 7207457mRNA:increased expression:kidney (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Myc  (MYC proto-oncogene, bHLH transcription factor)

Genes (Mus musculus)
Myc  (myelocytomatosis oncogene)

Genes (Homo sapiens)
MYC  (MYC proto-oncogene, bHLH transcription factor)


Additional Information