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dc.contributor.authorWandler, Anica M.
dc.date.accessioned2012-10-26T18:25:01Z
dc.date.available2012-10-26T18:25:01Z
dc.date.issued2012
dc.identifier.urihttp://hdl.handle.net/1794/12477
dc.description99 pagesen_US
dc.description.abstractUpon colonization of the human stomach, Helicobacter pylori establishes intimate interactions with the gastric epithelium, resulting in pathogenic host responses that can lead to gastric cancer. An important component of this interaction is translocation of the CagA effector protein into host cells, where it manipulates several conserved signaling pathways. Experiments in tissue culture cells have shown that CagA activates the phosphatase SHP-2, a component of receptor tyrosine kinase (RTK) pathways whose overactivation is associated with cancer formation. CagA has been proposed to function as a prokaryotic mimic of the eukaryotic Gab adaptor protein, which normally activates SHP-2. We developed a transgenic Drosophila melanogaster model to investigate whether CagA can function in a Gab-dependent process: specification of photoreceptor cells in the eye. We demonstrate that CagA expression is sufficient to rescue photoreceptor development in the absence of the Gab homologue through a mechanism that requires Drosophila SHP-2, demonstrating that CagA functions as a Gab protein in vivo and providing insight into CagA’s oncogenic potential. In addition to its function in RTK signaling, we explore CagA’s interactions with other host cell signaling pathways using the transgenic Drosophila model. We show that expressing CagA in the simple model epithelium created during wing development triggers apoptosis through activation of JNK signaling. We demonstrate that loss of several upstream JNK pathway components, including neoplastic tumor suppressors and the homolog of tumor necrosis factor, enhances CagA-induced cell death. Using a Drosophila model of metastasis we show that CagA enhances growth and invasion of tumors generated by expression of oncogenic Ras through JNK activation, implicating this pathway as an important driver of human gastric cancer progression. Finally, we use our transgenic Drosophila model to examine a role for CagA in disrupting the gastrointestinal ecosystem. We show that expressing CagA in adult intestinal stem cells is sufficient to significantly enhance epithelial proliferation, increase the production of antimicrobial peptides, and alter the intestinal bacterial community. This dissertation includes both previously published and unpublished co-authored material.en_US
dc.description.sponsorshipCommittee in charge: Kenneth E. Prehoda, Chair; Karen J. Guillemin, Advisor; Christopher A. Doe, Member; Tom H. Stevens, Member; Victoria G. Herman, Outside Member, Kimberly Andrews Espy, Memberen_US
dc.language.isoen_USen_US
dc.publisherUniversity of Oregonen_US
dc.relation.ispartofseriesUniversity of Oregon theses, Dept. of Chemistry, Ph. D., 2012;
dc.rightsrights_reserveden_US
dc.titleInvestigating Pathogenic Mechanisms of the Helicobacter pylori Virulence Factor CagA Using Transgenic Expression in Drosophila melanogasteren_US
dc.typeThesisen_US


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