title: Polycystic kidneys caused by sustained expression of Cux1 isoform p75.
abstract: 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.
authors: Department of Biochemistry, McGill University, Montreal H3G 1Y6 Canada.
authors: Chantal
authors: C
authors: Cadieux
authors: Ryoko
authors: R
authors: Harada
authors: Marilène
authors: M
authors: Paquet
authors: Olivier
authors: O
authors: Côté
authors: Marie
authors: M
authors: Trudel
authors: Alain
authors: A
authors: Nepveu
authors: Maxime
authors: M
authors: Bouchard
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000502:physiology*; D006720:Homozygote; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000737:chemistry* / Q000502:physiology*; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000737:chemistry* / Q000502:physiology*
chemical_list: C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins