Herbert T. Cohen, MD
Our laboratory is addressing neoplasia in the kidney, specifically renal cancer and renal cystic disease. We began by studying the von Hippel-Lindau (VHL) tumor suppressor pVHL. The (VHL) gene is mutated in all cases of von Hippel-Lindau disease, a rare familial cancer syndrome in which renal cysts and renal-cell carcinomas arise. The (VHL) gene was found mutated in the majority of cases of sporadic renal-cell carcinoma. To understand the role of p(VHL) as a renal tumor suppressor, we sought pVHL-interacting proteins. We identified Jade-1 as a novel protein that interacts strongly with pVHL. Jade-1 is the first member of a small family of Jade proteins with plant homeodomains and PEST protein degradation motifs. Jade homologs are conserved evolutionarily down to yeast, supporting their importance. Vertebrate proteins Jade1, Jade2 and Jade3 are now designated in GenBank databases. Interestingly, Jade-1 is stabilized by p(VHL). As a protein upregulated by a tumor suppressor, Jade-1 has tumor suppressor properties itself, as it inhibits cell growth and promotes apoptosis. Furthermore, p(VHL) mutations associated with renal cancer fail to stabilize Jade-1, suggesting a link to disease pathogenesis. Jade-1 has transcriptional activation, histone acetylation, and ubiquitin ligase activity. As a further link to renal cystic disease, Jade-1 is intricately regulated by polycystin-1, product of the autosomal dominant polycystic kidney disease gene PKD1. Even subtle disease-causing mutations in polycystin-1 block Jade-1 regulation. Thus, Jade-1 is a key signaling target in multiple causes of renal neoplasia and likely participates in the pathogenesis of renal cancer and renal cystic disease.