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Neurofibromatosis type I (NF1) is a familial multisystem disease that occurs in approximately one in 3,500 people designating it as one of the most common autosomal-dominant human diseases. Approximately 5% of all NF1 patients develop malignant tumors making it the most common tumor-predisposing disease in humans. Mutations in the NF1 gene, which functions as a tumor suppressor, are considered to be the primary cause for the disease. NF1 is a very large protein composed of 2818 amino acids. A small segment of the protein has been demonstrated to function as a negative regulator of the Ras family of small GTPases. However the biochemical functions of the remaining protein remains currently unknown. Thus, it seems likely that NF1 mediates its tumor suppressor activities through Ras-dependent as well as Ras-independent mechanisms. Therefore, we propose to determine what changes in gene expression occur as a result of loss of NF1 expression and to determine which expression changes are a consequence of Ras activity and which are not. We believe this information will lead to a more complete understanding of how NF1 mediates tumorigenesis and identify novel targets for the rational design of anti-cancer therapeutics against neurofibromatosis.

Recent genetic understanding has identified the gene NF1 to be disrupted or mutated in patients affected with NF1 resulting in reduced expression of the protein neurofibromin. One function of NF1 has shown that it acts to negatively regulate, or turn off, positive signals in the cell that direct the cell to proliferate. Specifically, NF1 turn the positive signals relayed by a protein called Ras. However, other studies have shown that NF1 may negatively regulate cell proliferation by mechanisms other than through inactivation of Ras. These other mechanisms however, are currently unknown. The purpose of the proposed study was to determine what changes in gene expression occur in cells from a patient with neurofibromatosis when we force these cells to express neurofibromin. The study was designed to identify and determine genes deregulated by NF1 in a Ras-dependent and Ras-independent manner. Taken together, these studies were designed to contribute to our understanding of the function and downstream effects NF1 has on the cell. In addition, determining the downstream nuclear events that occur in response to NF1 may provide novel targets for the treatment of NF1 associated cancers.