Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Polycystin-1 and polycystin-2 regulate the cell cycle through the helix–loop–helix inhibitor Id2

Nature Cell Biology volume 7, pages 1202–1212 (2005)Cite this article

An Erratum to this article was published on 02 December 2005

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PC2 expression regulates the cell cycle in 293T cells.
Figure 2: PC2 interacts with Id2.
Figure 3: PC2 modulates Id2 nuclear translocation in 293T cells.
Figure 4: Inter-relationship among Id2, PC2 and PC1.
Figure 5: PC2 regulates the Id2–p21–Cdk2 pathway.
Figure 6: PC1 mutation disrupts the PC2–Id2 interaction.
Figure 7: PC2 regulates the Id2–E47 protein complex.
Figure 8: Id2RNAi and cell cycle.

Similar content being viewed by others

References

  1. Gabow, P. A. Autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 22, 511–512 (1993).

    Article  CAS  Google Scholar 

  2. Nadasdy, T. et al. Proliferative activity of cyst epithelium in human renal cystic diseases. J. Am. Soc. Nephrol. 5, 1462–1468 (1995).

    CAS  PubMed  Google Scholar 

  3. Grantham, J. J. Homer Smith Award. Fluid secretion, cellular proliferation, and the pathogenesis of renal epithelial cysts. J. Am. Soc. Nephrol. 3, 1841–1857 (1993).

    CAS  PubMed  Google Scholar 

  4. Grantham, J. J. Polycystic kidney disease: from the bedside to the gene and back. Curr. Opin. Nephrol. Hypertens. 10, 533–542 (2001).

    Article  CAS  Google Scholar 

  5. Calvet, J. P. Injury and development in polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 3, 340–348 (1994).

    Article  CAS  Google Scholar 

  6. Wilson, P. D. Epithelial cell polarity and disease. Am. J. Physiol. 272, F434–F442 (1997).

    CAS  PubMed  Google Scholar 

  7. The International Polycystic Kidney Disease Consortium. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81, 289–298 (1995).

  8. Hughes, J. et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genet. 10, 151–160 (1995).

    Article  CAS  Google Scholar 

  9. Delmas, P. et al. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J. Biol. Chem. 277, 11276–11283 (2002).

    Article  CAS  Google Scholar 

  10. Parnell, S. C. et al. Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. J. Biol. Chem. 277, 19566–71952 (2002).

    Article  CAS  Google Scholar 

  11. Stayner, C. & Zhou, J. Polycystin channels and kidney disease. Trends Pharmacol. Sci. 22, 543–546 (2001).

    Article  CAS  Google Scholar 

  12. Vassilev, P. M. et al. Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease. Biochem. Biophys. Res. Commun. 282, 341–350 (2001).

    Article  CAS  Google Scholar 

  13. Gonzalez-Perrett, S. et al. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc. Natl Acad. Sci. USA 98, 1182–1187 (2001).

    Article  CAS  Google Scholar 

  14. Koulen, P. et al. Polycystin-2 is an intracellular calcium release channel. Nature Cell Biol. 4, 191–197 (2002).

    Article  CAS  Google Scholar 

  15. Qian, F. et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet. 16, 179–183 (1997).

    Article  CAS  Google Scholar 

  16. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V. P. & Walz, G. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Natl Acad. Sci. USA 94, 6965–6970 (1997).

    Article  CAS  Google Scholar 

  17. Lakkis, M. & Zhou, J. Molecular complexes formed with polycystins. Nephron 93, E3–E8 (2003).

    Article  CAS  Google Scholar 

  18. Li, Q. et al. Polycystin-2 associates with tropomyosin-1, an actin microfilament component. J. Mol. Biol. 325, 949–962 (2003).

    Article  CAS  Google Scholar 

  19. Li, Q., Shen, P. Y., Wu, G. & Chen, X. Z. Polycystin-2 interacts with troponin I, an angiogenesis inhibitor. Biochemistry 42, 450–457 (2003).

    Article  CAS  Google Scholar 

  20. Luo, Y., Vassilev, P. M., Li, X., Kawanabe, Y. & Zhou, J. Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol. Cell. Biol. 23, 2600–2607 (2003).

    Article  CAS  Google Scholar 

  21. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet. 33, 129–137 (2003).

    Article  CAS  Google Scholar 

  22. Lu, W. et al. Perinatal lethality with kidney and pancreas defects in mice with a targeted Pkd1 mutation. Nature Genet 17, 179–181 (1997).

    Article  CAS  Google Scholar 

  23. Lu, W. et al. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum. Mol. Genet. 10, 2385–2396 (2001).

    Article  CAS  Google Scholar 

  24. Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

    Article  CAS  Google Scholar 

  25. Delmas, P. et al. Gating of the polycystin ion channel signaling complex in neurons and kidney cells. FASEB J. 18, 740–742 (2004).

    Article  CAS  Google Scholar 

  26. Murre, C. et al. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58, 537–544 (1989).

    Article  CAS  Google Scholar 

  27. Prabhu, S., Ignatova, A., Park, S. T. & Sun, X. H. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol. Cell. Biol. 17, 5888–5896 (1997).

    Article  CAS  Google Scholar 

  28. Peverali, F. A. et al. Regulation of G1 progression by E2A and Id helix-loop-helix proteins. EMBO J. 13, 4291–4301 (1994).

    Article  CAS  Google Scholar 

  29. Pagliuca, A., Gallo, P., De Luca, P. & Lania, L. Class A helix-loop-helix proteins are positive regulators of several cyclin-dependent kinase inhibitors' promoter activity and negatively affect cell growth. Cancer Res. 60, 1376–1382 (2000).

    CAS  PubMed  Google Scholar 

  30. Fields, S. & Song, O. A novel genetic system to detect protein-protein interactions. Nature 340, 245–246 (1989).

    Article  CAS  Google Scholar 

  31. Kim, E. et al. The polycystic kidney disease 1 gene product modulates Wnt signaling. J. Biol. Chem. 274, 4947–4953 (1999).

    Article  CAS  Google Scholar 

  32. Bhunia, A. K. et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109, 157–168 (2002).

    Article  CAS  Google Scholar 

  33. Hara, E., Hall, M. & Peters, G. Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors. EMBO J. 16, 332–342 (1997).

    Article  CAS  Google Scholar 

  34. Matsumura, M. E., Lobe, D. R. & McNamara, C. A. Contribution of the helix-loop-helix factor Id2 to regulation of vascular smooth muscle cell proliferation. J. Biol. Chem. 277, 7293–7297 (2002).

    Article  CAS  Google Scholar 

  35. Trudel, M., Barisoni, L., Lanoix, J. & D'Agati, V. Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression. Am. J. Pathol. 152, 219–229 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Reeders, S. T. Multilocus polycystic disease. Nature Genet. 1, 235–237 (1992).

    Article  CAS  Google Scholar 

  37. Qian, F., Watnick, T. J., Onuchic, L. F. & Germino, G. G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87, 979–987 (1996).

    Article  CAS  Google Scholar 

  38. Rockman, S. P. et al. Id2 is a target of the β-catenin/T cell factor pathway in colon carcinoma. J. Biol. Chem. 276, 45113–45119 (2001).

    Article  CAS  Google Scholar 

  39. Kondo, M. et al. A role for Id in the regulation of TGF-β-induced epithelial-mesenchymal transdifferentiation. Cell Death Differ. 11, 1092–1101 (2004).

    Article  CAS  Google Scholar 

  40. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).

    Article  CAS  Google Scholar 

  41. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998).

    Article  CAS  Google Scholar 

  42. Trudel, M. et al. C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent. J. Exp. Med. 186, 1873–1884 (1997).

    Article  CAS  Google Scholar 

  43. Deed, R. W., Jasiok, M. & Norton, J. D. Attenuated function of a variant form of the helix-loop-helix protein, Id-3, generated by an alternative splicing mechanism. FEBS Lett. 393, 113–116 (1996).

    Article  CAS  Google Scholar 

  44. Kowanetz, M., Valcourt, U., Bergstrom, R., Heldin, C. H. & Moustakas, A. Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor β and bone morphogenetic protein. Mol. Cell. Biol. 24, 4241–4254 (2004).

    Article  CAS  Google Scholar 

  45. Kurooka, H. & Yokota, Y. Nucleo-cytoplasmic shuttling of Id2, a negative regulator of basic helix-loop-helix transcription factors. J. Biol. Chem. 280, 4313–4320 (2005).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

  1. Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA

    Xiaogang Li, Ying Luo, Patrick G. Starremans & Jing Zhou

  2. Cardiovascular Division, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, 22908, VA, USA

    Coleen A. McNamara

  3. Division of Nephrology, Department of Medicine, Toronto Hospital and University of Toronto, Toronto, M5G2C4, Ontario, Canada

    York Pei

Authors
  1. Xiaogang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick G. Starremans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Coleen A. McNamara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. York Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Zhou.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figure S1 (PDF 123 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1326

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing