Identification of novel tumor suppressor genes

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): We have conducted a genetic screen that can identify mutations that give cells even a subtle proliferative advantage over their wild-type neighbors. In a screen of the four major autosomal arms of Drosophila, we have identified mutations in more than 23 loci. Several of these loci encode homologs of known mammalian tumor suppressor genes including PTEN and the two genes mutated in tuberous sclerosis in humans (TSC1 and TSC2). This proposal describes experiments aimed at the characterization of several new genes identified in this screen including salvador, minotaur, and malthus. Each of these mutations results in increased representation of mutant tissue at the expense of wild-type tissue. Mutations in salvador result in sustained cell proliferation after wild-type cells have stopped dividing. Mutant cells appear to be resistant to apoptosis. The salvador gene encodes a novel protein that has highly conserved homologs in humans and C. elegans. Specific Aim 1 of this proposal is aimed at characterizing the phenotypic properties of salvador mutants including a detailed characterization of the cycling properties of mutant cells. Other experiments are aimed at identifying genes that interact with salvador using yeast two-hybrid screens and genetic screens in Drosophila. Specific Aim 2 describes experiments that are aimed at a phenotypic and molecular characterization of the minotaur and malthus genes as well as other genes identified in the screen. The growth properties of mutant tissue will be investigated in developing imaginal discs. The genes will be mapped and cloned. Specific Aim 3 details studies that characterize the human orthologs of genes identified in the screen. The effect of overexpression in tissue culture cells will be investigated. Their expression pattern will be determined. Human cancer cell lines will be analyzed for mutations in these genes. The experiments described in this proposal will provide insights into the mechanisms that restrict tissue growth and cell numbers during Drosophila development and will also determine the function of their human homologs in tumorigenesis.