Several diseases have been identified in which defects in protein folding are directly responsible for the pathological state. We have recently discovered that TRiC and Hsc70 participate in the biogenesis of the tumor suppressor protein VHL, which is mutated in most renal carcinomas. Importantly, we find that a number of tumor causing mutations result in an impaired interaction with the chaperone machinery and thus defective VHL folding. Interestingly, it appears that VHL folding is coupled to its incorporation into an oligomeric assembly involved in ubiquitin-mediated degradation. Thus, our results indicate that the cytosolic chaperone machinery is also involved in mediating, and perhaps regulating, the assembly of oligomeric complexes.

Mutations in the human VHL gene are linked to a hereditary cancer syndrome newly diagnosed in over 20,000 Americans each year. The disease is autosomal dominant and affected individuals develop a variety of benign or malignant tumors in a number of organs, including kidney (renal cell carcinomas), retina (retinal angiomas), central nervous system (CNS hemangioblastomas), pancreas (pancreatic cysts), and the adrenal gland (pheochromocytomas). The molecular basis for the tumor suppressor activity of VHL is poorly understood. Current evidence suggests that its activity is mediated through VHL binding to the cellular proteins elongin B and elongin C. The VHL-BC complex appears to be function as part of a ubiquitin-ligase complex in the selective targeting of yet undefined substrates for ubiquitin-dependent degradation.

We are currently investigating the role of protein folding in the regulation of wild type VHL activity, and how protein folding is affected in a number of tumor-causing mutations. Our approach combines in vitro and in vivo experiments.