The reproducible pattern of organismal growth during metazoan development is the product of genetically controlled signaling pathways/Patterned activation of these pathways shapes developing organs, and defects in their regulation can contribute to hyperplastic phenotypes like cancer. A long-term goal of our research program is to identify and characterize growth-inhibitory genes using the fruit fly Drosophila melanogaster as a model system of metazoan development. We anticipate that in some cases, these genes will encode the fly orthologs of mammalian tumor suppressors, and that our work will thus provide a model for the roles of these genes in human disease. One such gene, called Tumor susceptibility gene-101 (Tsg101), is the subject of the work proposed here. Almost ten years ago, it was shown that functional inactivation of Tsg101 causes cultured mouse cells to display features of oncogenic transformation. However, the mechanisms underlying this effect have remained very poorly understood. Recently, we isolated mutations in the Drosophila ortholog of the human Tsg101 gene (referred to as Tsg101) based upon their surprising ability to provoke overgrowth phenotypes in the developing fly eye. Using this system as a model of Tsg101 function, we have identified two downstream targets of Tsg101 mutations: one is a non-cell autonomous pathway involving ectopic activation of the Notch receptor and expression of unpaired, the secreted ligand of the Jak-STAT pathway;the second involves the Crumbs protein, an established component of cell polarity regulatory complexes, and is associated with cell-autonomous defects in epithelial polarity and tissue architecture.
The aims of this proposal are an extension of these findings. Notch appears to be a critical effector of Tsg101 mutant phenotypes, and in Aim 1, we will investigate the molecular mechanism through which Tsg101 mutations activate the Notch receptor.
In Aim 2, we propose to investigate the mechanism through which Tsg101 controls Crumbs, and to use genetic techniques test the hypothesis that Tsg101 mutations alter Crumbs activity in vivo. And in Aim 3, we will use genetic and biochemical techniques to test the hypothesis that Tsg101 mutations trigger eye hyperplasia by activating one or more of the major growth regulatory pathways in Drosophila (Tsc/Tor, insulin, Ras, Myc, and CyclinD).
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