The VHL gene was first identified in 1993 as the gene responsible for a rare inherited cancer syndrome called Von Hippel-Lindau disease. Inheritance of a single defective VHL gene results in the predisposition to the development of a variety of cancers including clear cell renal carcinoma, pheochromocytoma, and CNS hemangioblastoma. Subsequently, it was shown that the majority of tumors derived from patients with sporadic clear cell renal carcinoma also contained both loss of heterozygosity of the VHL locus and failure of expression and/or mutations in the remaining VHL allele. The goal of this project is to understand the biochemistry and cell biology of the VHL gene product and thereby to elucidate its role in cell transformation. Our previous studies include the completion of the cloning and sequencing of the human and rat VHL gene, the biochemical characterization of the gene product and its intracellular localization. The identification and cloning of gene products that VHL interacts with has illuminated an unexpected new area of gene control--the regulation of transcriptional elongation. We have continued our characterization of the interaction between the VHL proteins and other cellular components. In order to identify new potential interacting proteins we utilized recombinant VHL-Elongin B/C complexes to affinity purify additional cellular interacting proteins. One of the proteins has been recently identified as a homolog of the new recognized Cullin family of proteins. Two other interacting proteins have been identified by far Western blot analysis which we are now attempting to clone by an expression approach. We have shown that VHL regulates the expression of vascular endothelial growth factor (VEGF) in a post-transcriptional manner. We are currently performing studies to identify the VEGF 3'UTR cis-element responsible for VHL-mediated regulation. We have extensively studied transport of the VHL protein and shown cell density and such factors as low serum conditions are critical to transport of VHL into and out of the nucleus. We have developed a knockout mouse model to determine VHL function in the mouse. Embryos homozygous for this mutation die in utero between 7 and 8.5 days. Ongoing studies suggest a failure of blood-island formation and vasculogenesis in the labyrinth of the yolk-sac.
