LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: Nature Publishing Group
Languages: English
Types: Article
Subjects: Article

Classified by OpenAIRE into

mesheuropmc: urogenital system, urologic and male genital diseases, female genital diseases and pregnancy complications
Identifiers:pmc:PMC2493387
Tubular cell proliferation occurs early and precedes cyst formation in autosomal dominant polycystic kidney disease (ADPKD). To identify key alterations in cell signalling which regulate cell proliferation in ADPKD, we examined the potential role of insulin-like growth factor-1 (IGF-1) mediated signalling pathways. Conditionally immortalised tubular epithelial cells were generated from ADPKD patients with characterised germline PKD1 mutations and normal individuals. Germline and somatic PKD1 (but not PKD2) mutations were identified in PKD1 cystic cells by DHPLC. All lines showed a reduction or absence of polycystin-1 but normal polycystin-2 expression. Polycystin-1 deficiency was associated with increased sensitivity to IGF-1 as well as a permissive effect of cAMP on cell growth. The increase in cell proliferation to both agents was dependent on PI3 kinase and ERK activity. Inhibition of Ras or Raf activity also abolished stimulated cell proliferation. Ras activation assays revealed significantly higher IGF-1 stimulated levels of GTP-Ras in cystic cells compared to control cells but cAMP alone had no effect on GTP-Ras levels. These results suggest that haploinsufficiency of PC1 may lower the threshold for activation of a Ras-Raf mediated signalling cascade leading to growth-factor induced hyperproliferation. Inhibition of Ras or Raf activation could be a useful therapeutic approach to reducing tubular cell proliferation in ADPKD.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164. [PubMed: 14711914]
    • 2. Ong AC, Harris PC. Molecular pathogenesis of ADPKD: The polycystin complex gets complex. Kidney Int 2005;67:1234-1247. [PubMed: 15780076]
    • 3. Calvet JP, Grantham JJ. The genetics and physiology of polycystic kidney disease. Semin Nephrol 2001;21:107-123. [PubMed: 11245774]
    • 4. Lanoix J, D'Agati V, Szabolcs M, Trudel M. Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). Oncogene 1996;13:1153- 1160. [PubMed: 8808689]
    • 5. Nadasdy T, Laszik Z, Lajoie G, et al. Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc Nephrol 1995;5:1462-1468. [PubMed: 7703384]
    • 6. Chang MY, Parker E, Ibrahim S, et al. Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models. Nephrol Dial Transplant 2006;21:2078-2084. [PubMed: 16720597]
    • 7. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 2005;16:46-51. [PubMed: 15563559]
    • 8. Aukema HM, Housini I. Dietary soy protein effects on disease and IGF-I in male and female Han:SPRD-cy rats. Kidney Int 2001;59:52-61. [PubMed: 11135057]
    • 9. Nakamura T, Ebihara I, Nagaoka I, et al. Growth factor gene expression in kidney of murine polycystic kidney disease. J Am Soc Nephrol 1993;3:1378-1386. [PubMed: 8094982]
    • 10. Wanke R, Hermanns W, Folger S, et al. Accelerated growth and visceral lesions in transgenic mice expressing foreign genes of the growth hormone family: an overview. Pediatr Nephrol 1991;5:513- 521. [PubMed: 1911131]
    • 11. Rossetti S, Chauveau D, Walker D, et al. A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int 2002;61:1588-1599. [PubMed: 11967008]
    • 12. Yamaguchi T, Nagao S, Wallace DP, et al. Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 2003;63:1983-1994. [PubMed: 12753285]
    • 13. Bhunia AK, Piontek K, Boletta A, 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 2002;109:157-168. [PubMed: 12007403]
    • 14. Nishio S, Hatano M, Nagata M, et al. Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation. J Clin Invest 2005;115:910-918. [PubMed: 15761494]
    • 15. Kim H, Bae Y, Jeong W, et al. Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition. Eur J Hum Genet 2004;12:433-440. [PubMed: 15054393]
    • 16. Sutters M, Yamaguchi T, Maser RL, et al. Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells. Kidney Int 2001;60:484-494. [PubMed: 11473631]
    • 17. Parnell SC, Magenheimer BS, Maser RL, et al. Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. J Biol Chem 2002;277:19566-19572. [PubMed: 11912216]
    • 18. Boca M, Distefano G, Qian F, et al. Polycystin-1 Induces Resistance to Apoptosis through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway. J Am Soc Nephrol. 2006
    • 19. Ong AC, Harris PC. Molecular basis of renal cyst formation--one hit or two? Lancet 1997;349:1039- 1040. [PubMed: 9107237]
    • 20. Ong AC, Harris PC, Davies DR, et al. Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. Kidney Int 1999;56:1324-1333. [PubMed: 10504485]
    • 21. Hanaoka K, Guggino WB. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol 2000;11:1179-1187. [PubMed: 10864573]
    • 22. Yamaguchi T, Pelling JC, Ramaswamy NT, et al. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 2000;57:1460-1471. [PubMed: 10760082]
    • 23. Yamaguchi T, Wallace DP, Magenheimer BS, et al. Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 2004;279:40419-40430. [PubMed: 15263001]
    • 24. Schaffner DL, Barrios R, Massey C, et al. Targeting of the rasT24 oncogene to the proximal convoluted tubules in transgenic mice results in hyperplasia and polycystic kidneys. Am J Pathol 1993;142:1051-1060. [PubMed: 8097368]
    • 25. Chang MY, Parker E, El Nahas M, et al. Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2007;18:560-569. [PubMed: 17202412]
    • 26. O'Hare MJ, Bond J, Clarke C, et al. Conditional immortalization of freshly isolated human mammary fibroblasts and endothelial cells. Proc Natl Acad Sci U S A 2001;98:646-651. [PubMed: 11209060]
    • 27. Streets AJ, Newby LJ, O'Hare MJ, et al. Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion. J Am Soc Nephrol 2003;14:1804-1815. [PubMed: 12819240]
    • 28. Rossetti S, Strmecki L, Gamble V, et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet 2001;68:46-63. [PubMed: 11115377]
    • 29. Ong AC, Ward CJ, Butler RJ, et al. Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue. Am J Pathol 1999;154:1721-1729. [PubMed: 10362797]
    • 30. Newby LJ, Streets AJ, Zhao Y, et al. Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex. J Biol Chem 2002;277:20763-20773. [PubMed: 11901144]
    • 31. Streets AJ, Moon DJ, Kane ME, et al. Identification of an N-terminal glycogen synthase kinase 3 phosphorylation site which regulates the functional localization of polycystin-2 in vivo and in vitro. Hum Mol Genet 2006;15:1465-1473. [PubMed: 16551655]
  • No related research data.
  • No similar publications.

Share - Bookmark

Funded by projects

  • WT | Polycystin-1 mediated cell a...

Cite this article