BETA-CATENIN, APC AND MYC SIGNALING IN DROSOPHILA

Princeton University, Princeton NJ

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Abstract

The long-term goal of this project is to use Drosophila genetic and molecular biology to understand cellular pathways of vertebrate oncogenes. Much of our past work has focused on the Drosophila homologue of beta-catenin (=Armadillo), a protein which functions in humans and flies both in adhesive junctions and as transcriptional co- activator in Wnt signaling. In the next five years, we will focus our analysis of these two roles and factors that control nuclear localization, transcriptional activation and cell adhesive function. We will carry out genetic screens to identify alleles defective for specific aspects of Arm function. We will test a model in which nuclear localization of Arm counters a cytoplasmic anchor that normally retains Arm in the nucleus. We will also investigate the interactions between Armadillo and the adenomatous polyposis coli protein (APC). We have cloned and characterized two Drosophila homologues of human APC and shown that null mutations in one of the genes cause apoptosis and cell shape defects in retinal neurons. We will investigate the cell biological basis for these phenotypes and investigate their relationship to Arm regulation. We will test for functional redundancy between the two APC-like Drosophila genes, and characterize the mechanisms responsible for their differing intracellular localizations. We also plan to initiate an analysis of the Myc pathway, focusing on components which have recently been reported to interact with beta- catenin. We will obtain loss of function alleles of Trap, Tip49 and Tip48 and characterize their effects on cell proliferation, growth and differentiation. Using transgenes that allow tissue specific expression of mutant and wildtype forms we will determine the consequences of misexpression on cell viability and differentiation. We will investigate the interaction between Tip49/48 and Armadillo, using strategies that allow Arm level, stabilization and transcriptional activity to be assayed in vivo in driving cells.