Renal cancer is a major cause of morbidity and mortality. Roughly 54,000 Americans will be diagnosed and about 13,000 will die from renal cancer this year. Defects in the von Hippel-Lindau disease gene VHL are found in the majority of renal cancers, making study of the pVHL protein a key starting point to understand the disease. We have identified Jade-1 as a pVHL interacting protein. Jade-1 is the first member of a Jade protein family that has plant homeodomains (PHDs) and PEST protein degradation sequences. PHD motifs may function in protein interactions, transcriptional activation, histone acetylation and ubiquitin ligase activity. Jade-1 has all these activities. Moreover, Jade-1 is stabilized by wild-type pVHL, but not by mutated forms of pVHL associated with renal cancer. Thus, the relationship between pVHL and Jade-1 correlates with renal cancer risk. As a protein upregulated by a tumor suppressor, Jade-1 has tumor suppressor properties itself. Of critical relevance to this proposal, we have found that Jade-1 binds and promotes the ubiquitination and destruction of beta-catenin and inhibits canonical Wnt signaling. Beta-catenin is a key oncoprotein. Moreover, pVHL inhibits beta-catenin and Wnt signaling through Jade-1. Furthermore, inhibitors of beta-catenin activity inhibit renal cancer cell growth. Thus, a new tumor suppressor pathway in renal cancer has been identified, the pVHL/Jade-1/beta-catenin axis. The following aims will be explored:
Aim 1 : The role of Jade-1 in renal cancer. As the major objective of this proposal, the direct role of Jade-1 in pVHL-mediated renal cancer and in renal cancer generally will be determined. Jade-1 null mice will be crossed with conditional Vhlh null mice, which get renal cysts, to determine the genetic interaction between these pathways. Jade-1 mice will be crossed with Tsc2 heterozygous mice, which get renal cystadenomas. The Jade-1 mice will be treated with chemical carcinogens. The role of Jade-1 in renal cancer growth will be examined in cell culture models as well. Additional substrates for Jade-1-mediated ubiquitination in renal cancer will be sought.
Aim 2 : The role of beta-catenin in renal cancer. The contribution of beta-catenin to renal tumorigenesis will be assessed in in vitro and in vivo studies. Importantly, a genetic interaction between Jade-1 and beta-catenin will tested using Jade-1 knockout mice and multiple intestinal neoplasia (Min) mice, which have a defect in the adenomatous polyposis coli (Apc) gene and have increased beta-catenin activity. The effect of inhibitors of the beta-catenin pathway will also be tested on renal cancer cells in vitro and in nude mice.
Aim 3 : The effect of pVHL on Jade-1 protein stability. The post-translational modifications of Jade-1 that are responsible for pVHL-mediated stabilization will be identified. This approach will focus on mass spectrometry.

Public Health Relevance

Renal cancer is an important, common clinical problem. We have identified a new tumor suppressor pathway involved in renal cancer that may be a target for intervention with drugs. This pathway involves the von-Hippel-Lindau tumor suppressor, the oncoprotein beta-catenin and a novel tumor suppressor protein identified in our laboratory called Jade-1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Medical Center
United States
Zip Code
Zeng, Liling; Bai, Ming; Mittal, Amit K et al. (2013) Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res 73:5371-80
Chitalia, Vipul C; Foy, Rebecca L; Bachschmid, Markus M et al. (2008) Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol 10:1208-16
Foy, Rebecca L; Song, Ihn Young; Chitalia, Vipul C et al. (2008) Role of Jade-1 in the histone acetyltransferase (HAT) HBO1 complex. J Biol Chem 283:28817-26
Basu, Aninda; Contreras, Alan G; Datta, Dipak et al. (2008) Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. Cancer Res 68:5689-98
Zhou, Mina I; Foy, Rebecca L; Chitalia, Vipul C et al. (2005) Jade-1, a candidate renal tumor suppressor that promotes apoptosis. Proc Natl Acad Sci U S A 102:11035-40
Cohen, Herbert T; McGovern, Francis J (2005) Renal-cell carcinoma. N Engl J Med 353:2477-90
Zhou, Mina I; Wang, Hongmei; Foy, Rebecca L et al. (2004) Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. Cancer Res 64:1278-86
Panchenko, Maria V; Zhou, Mina I; Cohen, Herbert T (2004) von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity. J Biol Chem 279:56032-41
Zhou, Mina I; Wang, Hongmei; Ross, Jonathan J et al. (2002) The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 277:39887-98
Cohen, H T (1999) Advances in the molecular basis of renal neoplasia. Curr Opin Nephrol Hypertens 8:325-31