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J. Biol. Chem., Vol. 283, Issue 20, 13817-13824, May 16, 2008

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Polycystic Kidneys Caused by Sustained Expression of Cux1 Isoform p75^*

Chantal Cadieux^¶, Ryoko Harada^¶, Marilène Paquet, Olivier Côté^||, Marie Trudel^||, Alain Nepveu^¶1, and Maxime Bouchard²

From the Department of Biochemistry, McGill Cancer Centre, ^¶Molecular Oncology Group of McGill University Health Center, McGill University, Montreal H3G 1Y6 and ^||Molecular Genetics and Development, Institut de Recherches Cliniques de Montréal, Facultéde Médecine de l'Université de Montréal, Montreal, Quebec H2W 1R7, Canada

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.

Received for publication, November 14, 2007 , and in revised form, March 18, 2008.

^* This work was supported by a grant from the National Cancer Institute of Canada (to M. B.) and a grant from the Canadian Institutes for Health Research (to A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel.: 514-934-1934 (ext. 35842); Fax: 514-843-1478; E-mail: alain.nepveu{at}mcgill.ca. ² To whom correspondence may be addressed. Tel.: 514-398-3532; Fax: 514-398-6769; E-mail: maxime.bouchard{at}mcgill.ca.

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