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.
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.
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