Role of Myc in the Growth Regulation Pathways

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DESCRIPTION (provided by applicant): Multifunctional processes that include endocrine regulation and production of growth factors and nutrients control growth, size and organ formation. IGFs/DILPs (Drosophila Insulin-like Peptides) and TOR (Target of Rapamycin) signaling pathways are important regulators of these processes as well as the Myc transcription factor. This application is directed towards understanding the molecular mechanisms that regulate dMyc expression in response to DILPs and TOR/Nutrient signaling and to identify the key events that control growth by dMyc in vivo. In our laboratory we have identified dMyc, the Drosophila homologue of the human myc proto-oncogene, as a down-stream effector in response to DILPs and TOR activity suggesting that dMyc may function as a sensor for growth in these signaling pathways. In addition, expression of dMyc in vivo, in specific metabolic tissues, increases organismal size. This last set of information provides a significant indication that dMyc may be able to regulate growth not only autonomously by inducing ribosomal biogenesis (mass) in the cells where it is expressed, but also that it may stimulate the production of "factors" that control growth of the organism, with a mechanism that is non cell-autonomous. The first aim is focused on studying how the activation of the DIPLs and TOR pathways regulates dMyc expression. We will use a combination of biochemical experiments using Drosophila S2 cells or in vivo in mitotic clones in larval imaginal discs to assess the relative contribution of amino acids or components of the insulin/DILPs or TOR signaling to dMyc protein and RNA expression. As IGFs/DILPs and TOR signaling pathways are regulated by phosphorylation events, our second aim is to study the events that regulate dMyc protein stability by its phosphorylation. We have identified, novel phosphorylation domains in dMyc protein important for its stability. We will characterize further these mutants by; a) in vitro analysis of their mechanism of phosphorylation by specific kinases; b) in vivo characterization of their regulation by DILPs, TOR signaling. These experiments are expected to define new functional domains for also for c-Myc. Our third specific aim is directed to identify the contribution of dMyc to organismal growth by; a) identification of the downstream signals which are activated in response to the autonomous and non-cell autonomous effects of dMyc; b) to identify the targets that are activated by dMyc in these metabolic tissues. In conclusion, the information obtained should greatly help in understanding not only Myc' s role in physiological growth, but also in pathological disorders such as metabolic diseases and cancer in vertebrates and in the long run provide useful new targets for therapeutic intervention. Public Health Relevance: Genetic or pathological conditions in the production of insulin and Growth Factors may cause metabolic disorders, such as diabetes, growth disorders or cancer. In our laboratory we are using the fruitfly Drosophila melanogaster as an animal model to study the processes that regulate these diseases. Drosophila has become a popular model organism for studying human disease since the discovery that 60% of these human disease genes have homologues in the fruitfly. We recently demonstrated that activation of the insulin pathway induces the expression of a gene named Myc. Myc is very important in human cells as it is one of the genes necessary for our cells to grow and proliferate. The Myc gene is also responsible for human pathological condition as its over-expression is one the major causes of human cancer. The possibility to use Drosophila as a model system to study Myc and its regulation by insulin and Growth Factors, offers an excellent alternative to mouse genetic to understand its function. With our research we expect to identify the mechanism that control growth in Drosophila in order to better understand metabolism and cancer in humans.