The initiation and progression of the tumorigenic capabilities of neoplastic cells involves genetic alterations which lead to the activation of oncogenes and the loss of function of tumor suppressor genes. The objective of this project is to identify, confirm, and characterize a tumor-suppressor (TS) gene localized to the long arm of chromosome 10 (10q23-24) that is intimately involved in the progression of gliomas to high grade glioblastoma multiforme (GMB). A strong candidate suppressor gene has recently been identified in the critical region. Deletion of large segments, or an entire copy, of chromosome 10 represents a very frequent (-90 percent) molecular alteration in GBMs and several other cancers. The hypothesis of the study proposes the loss of function of a tumor suppressor gene on chromosome 10 directly contributes to the progression of these cancers. The candidate TS gene cloned at the critical region appears to encode for a novel protein tyrosine phosphatase (PTPase), implicating a potential role of the candidate TS gene in cell signaling. They have previously used a functional approach in microcell-mediated chromosomal transfer to demonstrate the presence and biological function of a TS gene on 10q involved in glioma oncogenesis. To further define the TS locus a series of three independent approaches were pursued to define a critical region, including the identification of homozygous deletions in gliomas cells. All three of the approaches and allelic deletion analysis of prostrate carcinomas directed the attention towards a single locus. A gene has now been cloned from this critical region and spans the homozygous deletions. Mutations to the gene in cultured glioma and prostrate cells along with alterations in several human tumor specimens have been observed. Motif analyses implicates the gene product as a novel PTPase. This proposal is directed at the characterization of the candidate TS gene. The tumor suppressive active of the candidate gene will be assessed by transfecting various constructs of the candidate gene into glioma cells. The mutation and as the possible presence and effect(s) of germline mutations. The proposed biochemical activity(s) of the candidate gene as a protein tyrosine phosphatase will be assessed. Furthermore, the effects of mutations on the proposed activity(s) and/or localization of the gene product will be addressed. Finally, the signaling pathway that the candidate TS gene may play a role in will be examined. This combination of functional and molecular approaches will demonstrate the functional activity of the candidate TS gene and initiate investigations into its mechanism(s) of action.
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