Inactivation of the adenomatous polyposis coli (APC) tumor suppressor triggers the development of the vast majority of colorectal carcinomas. Our goal is to dissect the function(s) of APC, and the molecular and cellular consequences of APC inactivation, in vivo. As APC has been evolutionary conserved from flies to humans, we have developed a sensitive genetic system in Drosophila to study APC function. Data from this model provided conclusive evidence that APC is required for the negative regulation of beta-catenin, the central transcriptional activator in the conserved Wnt/Wingless (Wg) signal transduction pathway. In addition, these data revealed that upon Apc loss, beta-catenin hyperactivation can induce not only cell proliferation and cell differentiation, but also apoptotic cell death. Our approach is to identify essential components that induce the response to Apc inactivation by isolating and characterizing mutations that attenuate the hyperactivation of Wg signaling that occurs upon Apc loss. These studies have led to the identification of five loci that are candidates to encode proteins that act in the Wg pathway. We have found that one of these mutants is an allele of legless, a required gene in Wg transduction. Our isolation of a legless mutant verifies the ability of the approach to detect genes required in Wg signaling. We have molecularly identified two of the other loci, and the goal of the proposed research is to further characterize these two genes. We anticipate that the accomplishment of this work will significantly extend models for Wg signaling and at the same time provide basic insight into how dramatically different cellular programs can be induced upon Apc inactivation. The great conservation of APC and most known members of the Wnt pathway from flies to humans indicates that the characterization of Apc itself, as well as its downstream effectors in Drosophila, may provide a better understanding of the disease processes that are induced by the inactivation of APC in humans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cell Development and Function Integrated Review Group (CDF)
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Yassin, Rihab R,
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Dartmouth College
Schools of Medicine
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Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit et al. (2018) APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Dev Cell 44:566-581.e8
Tacchelly-Benites, Ofelia; Wang, Zhenghan; Yang, Eungi et al. (2018) Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC. PLoS Genet 14:e1007178
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Wang, Zhenghan; Tacchelly-Benites, Ofelia; Yang, Eungi et al. (2016) Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling. PLoS Genet 12:e1006494
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