Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by progressive cyst formation and ultimate loss of renal function. Increased cell proliferation is a key feature of the disease. Here, we show that the ADPKD protein polycystin-2 (PC2) regulates the cell cycle through direct interaction with Id2, a member of the helix–loop–helix (HLH) protein family that is known to regulate cell proliferation and differentiation. Id2 expression suppresses the induction of a cyclin-dependent kinase inhibitor, p21, by either polycystin-1 (PC1) or PC2. The PC2–Id2 interaction is regulated by PC1-dependent phosphorylation of PC2. Enhanced Id2 nuclear localization is seen in human and mouse cystic kidneys. Inhibition of Id2 expression by RNA interference corrects the hyperproliferative phenotype of PC1 mutant cells. We propose that Id2 has a crucial role in cell-cycle regulation that is mediated by PC1 and PC2.
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Acknowledgements
We thank W.C. Forrester and J. Hasskarl for discussions; G. Sui, M.E. Matsumura, Q. Xi, P. Finnerty and A. Beck for technical assistance; V. Torres for some human tissues; and S. Somlo for the PC2-S812A construct. This work was supported by grants from the National Institutes of Health to J.Z. (DK53357 for PC2, DK40703 for PC1 and DK51050 for mouse work), and a Postdoctoral Fellowship from the Polycystic Kidney Disease Foundation (X.L.).
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Li, X., Luo, Y., Starremans, P. et al. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix–loop–helix inhibitor Id2. Nat Cell Biol 7, 1202–1212 (2005). https://doi.org/10.1038/ncb1326
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DOI: https://doi.org/10.1038/ncb1326
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