Abstract 4021: Genetic studies identify a map of redox signaling pathways in Drosophila

Abstract

Abstract Altered redox signaling, a consequence of oxidative stress and hypoxia, is seen in many human cancers and there is compelling evidence that altered redox signaling leads to tumorigenesis and aggressive tumor growth. In order to survive redox stress, tumor cells must initiate an adaptive response that facilitates both survival and drug resistance. The response to oxidative stress is largely restricted to tumor cells and thus offers a selective target for drug development. While it is clear that redox signaling is an important cellular response, our understanding of redox signaling pathways is rudimentary, and a map of redox signaling pathways comparable to that for protein phosphorylation is not available. In order to identify novel redox signaling genes we have undertook a classical dominant modifier screen in Drosophila melanogaster. Redox homeostasis is maintained in humans and Drosophila by scavenger systems such as superoxide dismutase (SOD), glutathione peroxidase and thioredoxin (Trx). In humans, Trx and glutathione are reduced and regenerated by thioredoxin reductase (Trxr) and glutathione reductase. Drosophila, and possibly insects in general, have only one glutathione/thioredoxin reductase gene encoded by the thioredoxin reductase-1 gene (Trxr-1). Thus, in Drosophila Trxr-1 serves as the starting point for all redox reactions in the cell and mutational disruption of the Trxr-1 gene leads to a genetically redox stressed animal suitable for screening. We screened a collection of second and third chromosome deficiency lines to identify genomic regions that dominantly suppress, or enhance the semi-lethal phenotype of Trxr-1 mutants. Our initial screen identified 18 genomic regions that dominantly suppress or enhance Trxr-1 mutants. We used overlapping deficiencies to validate and narrow down 9 genomic regions and have identified six individual genes with multiple alleles that show suppressing or enhancing phenotypes in four of these regions including mutations in two genes associated with lipid signaling and the Toll-like receptor, 18-Wheeler. The identification of 18-Wheeler indicates that the screen was successful, as 18-Wheeler, in addition to playing a critical role in the Drosophila immune response, is a member of the redox-regulated NF-κB pathway. This screen identified several genes not previously known to be involved in redox signaling, and begins to define a map of redox signaling pathways likely conserved through evolution. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4021.