Department of Pathology and Laboratory Medicine Spring 2015 Seminar Series: Friday, February 6,
Herbert T. Cohen, MD
Tel (617) 638-7322
Fax (617) 638-7326
Pennsylvania State University, BS
Jefferson Medical College, MD
Rush Medical College, Residency in Internal Medicine
University of Chicago, Fellowship in Nephrology
Beth Israel Deaconess Medical Center and Harvard Medical School, Postdoctoral fellowship
Dr. Cohen’s laboratory is addressing the molecular basis of renal cancer, renal cystic disease and renal development and offers special expertise in gene expression mechanisms, signal transduction, protein-protein interactions, transcription factors, and renal epithelial cell biology. The laboratory has identified the first member of new protein family, the Jade family of proteins, on the basis of its interaction with the von Hippel-Lindau tumor suppressor pVHL. pVHL protein is a key component of the cellular oxygen-sensing system. The VHL gene is also the major renal cancer gene in adults. Jade-1 is a novel, growth suppressive plant homeodomain transcription factor that is the first protein found to be stabilized by pVHL. Jade-1 is also a ubiquitin ligase and key component of histone acetylation complexes. Interestingly, Jade-1 is stabilized by VHL protein in a manner that correlates with risk of renal manifestations in von Hippel-Lindau disease, which includes a cystic renal disease phenotype. A wider role for Jade-1 in renal cyst formation was therefore sought. Jade-1 is regulated by the product of the major gene for autosomal dominant polycystic kidney disease (ADPKD), polycystin-1, in a manner that is also disease relevant and physiologic. Importantly, Jade-1 serves as a critical ubiquitin ligase for the oncoprotein beta-catenin, which also plays critical roles in renal cancer, renal cyst formation and renal development. In part by controlling transcription and beta-catenin ubiquitination, Jade-1 and related family members are likely to be important in many contexts.
Cancer biology and epithelial cell biology approaches, advanced molecular biology approaches, protein-protein interactions, yeast 2-hybrid screening, protein ubiquitination assays, protein-DNA interactions, transcription assays, gene expression mechanisms including microarrays, confocal microscopy, transgenic and knockout mouse models
- 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.
- 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.
- 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 64:1278-1286.
- 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 279:56032-56043.
- 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-F866.
- 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.
- Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005 353:2477-2490.
- 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.
- 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.
- 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 (in press)
- 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)