Molecular Biology of Renal Cancer, Polycystic Kidney Disease, and Renal Development (Dr. Cohen)

Dr. Cohen’s laboratory is focusing on the molecular basis of renal cancer, renal cystic disease and renal development and offers special expertise in gene expression mechanisms, protein-protein interactions, transcription factors and transcription factor cloning, and renal epithelial cell biology. The laboratory is currently exploring the molecular mechanisms of tumor suppression by pVHL, the von Hippel-Lindau tumor suppressor. In addition to being the causative gene for von Hippel-Lindau disease, the VHL gene is the most commonly affected gene in sporadic renal cancer. The clinical manifestations of VHL disease include several types of vascular tumors and epithelial cysts, including clear-cell renal cancer and renal cysts.

Dr. Cohen’s laboratory has identified the first member of a small family of transcription factor proteins called the Jade family of proteins. Jade-1 protein interacts with pVHL and is a candidate renal tumor suppressor itself. Intriguingly, loss of stabilization of Jade-1 protein by pVHL correlates with the risk of development of renal cancer, suggesting it is important in renal cancer pathogenesis. Jade-1 directly promotes the ubiquitination and degradation of the oncoprotein beta-catenin, providing a mechanism for Jade-1-mediated tumor suppression and directly linking the pVHL tumor suppressor and Wnt oncogenesis pathways, as recently reported in Nature Cell Biology. Jade-1 is also strongly regulated by the products of the autosomal dominant polycystic kidney disease (ADPKD) genes, the polycystins. Thus, Jade-1 may play a wider role in renal cystogenesis. This work may also have important implications for vascular and renal development.

References

  1. Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT: The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 2002: 277:39887-39898.
  2. Lenburg ME, Liou LS, Gerry NP, Frampton GM, Cohen HT, Christman MF: Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 2003 3:31-43.
  3. Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT: Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and Is VHL mutation dependent. Cancer Res. 2004 64:1278-86.
  4. Panchenko MV, Zhou MI, Cohen HT: von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity. J Biol Chem. 2004 31;279:56032-41
  5. Xu H, Tian W, Lindsley JN, Oyama TT, Capasso JM, Rivard CJ, Cohen HT, Bagnasco SM, Anderson S, Cohen DM: EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo. Am J Physiol Renal Physiol. 2005: 288:F855-66.
  6. Lenburg ME, Liou LS, Gerry NP, Frampton GM, Cohen HT, Christman MF: Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 2003 3:31-43.
  7. Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT: Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and Is VHL mutation dependent. Cancer Res. 2004 64:1278-86.
  8. Panchenko MV, Zhou MI, Cohen HT: von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity. J Biol Chem. 2004 31;279:56032-41
  9. Xu H, Tian W, Lindsley JN, Oyama TT, Capasso JM, Rivard CJ, Cohen HT, Bagnasco SM, Anderson S, Cohen DM: EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo. Am J Physiol Renal Physiol. 2005: 288:F855-66.
  10. Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang H, Cohen HT: Jade-1, a candidate renal tumor suppressor that promotes apoptosis. Proc Natl Acad Sci USA. 2005 102:11035-11040.
  11. Cohen HT, McGovern FJ: Renal-cell carcinoma.N Engl J Med. 2005 353:2477-90.
  12. Nolan VG, Ma Q, Cohen HT, Adewoye A, Rybicki AC, Baldwin C, Mahabir RN, Homan EP, Wyszynski DF, Fabry ME, Nagel RL, Farrer LA, Steinberg MH: Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B. Am J Hematol 2007 82:179-184.
  13. Basu A, Contreras AG, Datta D, Flynn E, Zeng L, Cohen HT, Briscoe DM, Pal S: Overexpression of vascular endothelial growth factor and development of post-transplantation cancer. Cancer Res 2008 68:5689-5698.
  14. Foy RL, Song IY, Chitalia VC, Cohen HT, Saksouk N, Cayrou C, Vaziri C, Côté J, Panchenko MV: Role of Jade-1 in the histone acetyltransferase (HAT) HBO1 complex. J Biol Chem. 2008 Oct 24;283:28817-26
  15. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH, Dominguez I, Cohen HT: Jade-1 inhibits Wnt signaling by ubiquitinating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nature Cell Biol 2008 10:1208-16.
  16. Foy RL, Chitalia VC, Panchenko MV, Boletta A, Qian F, Piontek K, Tsiokas L, Zhou MI, Germino GG, Cohen HT: Polycystin-1 regulates the stability and ubiquitination of transcriptional coactivator Jade-1. (in revision)
Primary teaching affiliate
of BU School of Medicine