Functional and Tissue Specific Effects of VHL Mutations

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DESCRIPTION (provided by applicant): The Von HippeI-Lindau (VHL) syndrome is an autosomal dominant disorder characterized by mutations in the VHL tumor suppressor gene. Genotype-phenotype correlation has been observed with specific point mutations in VHL corresponding to the patterns of tumorigenesis. VHL type 1 disease displays clear cell renal cell carcinoma and cerebellar hemangioblastoma. VHL type 2 disease is defined by the presence of pheochromocytoma and is subdivided into type 2A (pheochromocytoma and hemangioblastoma), 2B (pheochromocytoma, renal cell cancer, and hemangioblastoma), and 2C (pheochromocytoma only). Mutations in VHL also occur in the majority of sporadic forms of clear cell renal cell carcinoma and hemangioblastoma. VHL has been implicated in cellular processes important for tumorigenesis including cell cycle control, response to oxygen deprivation, and angiogenesis. The importance of VHL in each of these processes as they pertain to tumorigenesis is unknown. To address this we propose the following hypothesis: VHL performs multiple functions within the cell, and perturbation of individual functions via specific missense mutations contributes to the tumor specificity of the VHL syndrome subtypes. By examining a panel of VHL mutations representative of the VHL disease subtypes in both tissue culture and genetically engineered animal model systems, this series of experiments will discriminate functions of VHL which determine tissue specific tumorigenesis. This proposal describes a 5-year training program to develop an academic career in cancer biology. The experiments described in the proposal will provide valuable experience in the use and manipulation of murine genetic model systems for the study of cancer under the mentorship of Dr. Celeste Simon. Dr. Simon is an associate professor in the Howard Hughes Medical Institute with extensive experience in the manipulation of animal model systems. In addition, the skills of Dr. Vicki Eng have been enlisted to enhance the training program in the pathologic evaluation of murine tumor models. Finally, an advisory committee of experienced and highly regarded medical scientists has been assembled to provide scientific and career advice. Ultimately, the time spent in the development of this project will allow the establishment of a line of inquiry in the fields of angiogenesis and tumorigenesis and will provide the skills necessary to become a successful independent investigator.