Genetic Disorders – Development
Kidney International (2005) 67, 432–442; doi:10.1111/j.1523-1755.2005.67099.x
Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice
MADHULIKA SHARMA1, JENNIFER G BRANTLEY1, NEAL I ALCALAY, JING ZHOU, ENGELA HEYSTEK, ROBIN L MASER and GREGORY B VANDEN HEUVEL
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas; Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Department of Medicine, Harvard Medical School, Boston, Massachusetts; and Department of Biology, Dordt College, Sioux Center, Iowa
Correspondence: Gregory B. Vanden Heuvel Ph.D., Department of Anatomy and Cell Biology, University of Kansas Medical Center, 2005 Wahl Hall East, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail:gvandenheuvel@kumc.edu
1These authors contributed equally to this work.
Received 23 December 2003; Revised 3 August 2004; Accepted 10 September 2004.
Abstract
Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice.
Background
Cux-1 is a murine homeodomain protein that functions as a cell cycle–dependent transcriptional repressor in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. In the kidney, Cux-1 is spatially and temporally regulated, and ectopic expression of Cux-1 in transgenic mice results in renal hyperplasia. Previously, we observed that Cux-1 is deregulated in cystic kidneys from cpk mice. Recent studies have suggested a role for the cyclin kinase inhibitor p21 in the development of polycystic kidney disease (PKD) in mice lacking PKD1.
Methods
Since p21 is a target of transcriptional repression by Cux-1, we compared the expression of Cux-1 and p21 in kidneys from Pkd1 null and cpk mice by immunohistochemistry and Western blotting. We also evaluated apoptosis and the expression of the cyclin kinase inhibitor p27 in Pkd1 null and cpk mice by terminal deoxynucleotidal transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining, immunohistochemistry, and Western blotting.
Results
In both early and late embryonic kidneys from Pkd1 null mice, Cux-1 was highly and ectopically expressed in normal-appearing tubule epithelium, interstitial cells, and in the epithelial cells lining the cysts, where it colocalized with proliferating cell nuclear antigen (PCNA). Increased Cux-1 expression in Pkd1 null kidneys was also associated with a decrease in p27 expression at late stages of cystogenesis. In cpk kidneys, Cux-1 was not up-regulated until late stages of cyst development. Moreover, in contrast to Pkd1 null kidneys, p21 and p27 were highly expressed in cpk kidneys. In late stages of cystogenesis, Cux-1 and p21 colocalized in cyst lining cells, which also showed a high incidence of apoptosis.
Conclusion
These results suggest that cyst development in Pkd1 null mice and cpk mice proceeds through different mechanisms. In Pkd1 null mice, ectopic expression of Cux-1 is associated with increased cell proliferation. In contrast, in cpk mice, ectopic expression of Cux-1 is associated with apoptosis.
Keywords:
Cux-1, CDP/Cux, polycystic kidney disease, p21, p27, cpk, Pkd1
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