The zebrafish is becoming an increasingly attractive cancer model as several oncogenes and tumor suppressor genes appear to have similar properties in fish as they do in mammals. An insertional mutagenesis screen to identify genes required for embryonic development in the zebrafish has led to a collection of hundreds of mutations for which the mutated genes have been identified. To date we have identified 18 genes whose mutation renders the fish highly susceptible to the development of an otherwise rare tumor type, malignant peripheral nerve sheath tumor. One of these genes is a zebrafish ortholog of the mammalian tumor suppressor neurofibromatosis type 2 (NF2), whose mutation can also lead to the development of tumors of neuronal origin. Surprisingly, the other 17 genes all encode ribosomal proteins (RPs), and molecular studies indicate that the rp genes function as haploinsufficient tumor suppressor genes. Preliminary analysis of the rp mutants, and also the known roles of the mammalian RPs, suggests two possible models to account for the rps' tumor suppressor function, defects in translational capacity and/or p53 signaling. Experiments in the proposal will test these models. First, zebrafish will be employed to better understand how the rp heterozygous mutations contribute to the development of tumors. Second, the relationship between the translation properties of the rp heterozygous mutants and their tumor suppressive activity will be established. Finally, the panel of zebrafish mutants, and parallel analysis in mammalian cells, will be used to establish how the RPs contribute to the regulation of p53 and, to determine the impact of this pathway on the tumorigenic process. ? ?
