REGULATION OF GROWTH AND PROLIFERATION BY DROSOPHILA TOR

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DESCRIPTION (applicant's description): The goal of this project is to understand the mechanisms that govern cell growth and proliferation during development. To this end, we propose genetic and molecular studies of dTOR, a Drosophila homolog of the yeast TOR and mammalian mTOR/FRAP protein kinases which have crucial roles in protein synthesis and cell cycle regulation. This project has four major aims. First, to determine how loss of dTOR activity results in cell cycle arrest, FACS analysis will be used to determine the cell cycle phases in which dTOR is required, and the activity and levels of candidate cell cycle regulators will be measured in dTOR mutant backgrounds. Second, we will determine the mechanisms by which dTOR signals to two of its well characterized targets, p70 S6 kinase and 4E-BP1. Third, we will use genetic and biochemical tests to determine how dTOR activity is regulated. We will distinguish between two alternative hypothesis: that dTOR is a target of the P13K signaling pathway, and that dTOR activity is regulated in response to nutrient levels. Fourth, these tests of candidate molecules will be complemented by genetic interaction screens aimed at identifying novel regulators and effectors of dTOR. We will screen for mutations that suppress dTOR phenotypes. The TOR protein and the growth pathways it regulates are highly conserved between flies and humans, and therefore we expect these studies to provide insights into growth control during human development, tissue homeostasis, and tumorigenesis.