Inactivation of the adenomatous polyposis coli (APC) tumor suppressor triggers the development of colorectal, duodenal, and gastric polyps and carcinoma. APC is a critical effector in the evolutionarily conserved Wnt/ss-catenin signal transduction pathway, which directs cell proliferation, differentiation, and death during metazoan development, and is aberrantly activated in several types of cancer. The objective of our research is to understand the mechanisms by which APC regulates the activity of the Wnt pathway. We have developed a powerful genetic system in Drosophila to study APC function, and to identify effectors that determine the cellular consequences of APC loss. Our findings have revealed, unexpectedly, that fly APC homologs have dual positive and negative regulatory roles in Wnt transduction that are mediated by structurally distinct domains. We found that in addition to a well-documented negative regulatory role in destabilizing ss-catenin, APC also promotes Wnt transduction by mediating the degradation Axin, a negative effector of Wnt signaling. We propose to determine the mechanisms by which APC mediates Axin degradation using a combination of genetic, cell biological, and biochemical approaches. In addition, we propose to characterize one regulator of the cellular response to Apc loss that was revealed in our genetic screens. We anticipate that this work will inform our understanding of APC function and Wnt signal transduction.

Public Health Relevance

The proposed studies aim to understand how inactivation of the Adenomatous polyposis coli (APC) tumor suppressor triggers the development of the majority of colorectal cancers. We will investigate the function of APC during normal development, and identify proteins that determine the cellular consequences of APC loss.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105038-08
Application #
8448989
Study Section
Intercellular Interactions (ICI)
Program Officer
Yassin, Rihab R,
Project Start
2003-12-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$246,543
Indirect Cost
$90,503
Name
Dartmouth College
Department
Genetics
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
Yang, Eungi; Tacchelly-Benites, Ofelia; Wang, Zhenghan et al. (2016) Wnt pathway activation by ADP-ribosylation. Nat Commun 7:11430
Wang, Zhenghan; Tian, Ai; Benchabane, Hassina et al. (2016) The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila. Development 143:1710-20
Wang, Zhenghan; Tacchelly-Benites, Ofelia; Yang, Eungi et al. (2016) Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase. Genetics 203:269-81
Tian, Ai; Benchabane, Hassina; Wang, Zhenghan et al. (2016) Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries. PLoS Genet 12:e1005822
Tacchelly-Benites, Ofelia; Wang, Zhenghan; Yang, Eungi et al. (2013) Toggling a conformational switch in Wnt/β-catenin signaling: regulation of Axin phosphorylation. The phosphorylation state of Axin controls its scaffold function in two Wnt pathway protein complexes. Bioessays 35:1063-70
Busch, Alexander M; Johnson, Kevin C; Stan, Radu V et al. (2013) Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer 13:211
Benchabane, Hassina; Xin, Nan; Tian, Ai et al. (2011) Jerky/Earthbound facilitates cell-specific Wnt/Wingless signalling by modulating β-catenin-TCF activity. EMBO J 30:1444-58
Xin, Nan; Benchabane, Hassina; Tian, Ai et al. (2011) Erect Wing facilitates context-dependent Wnt/Wingless signaling by recruiting the cell-specific Armadillo-TCF adaptor Earthbound to chromatin. Development 138:4955-67
Benchabane, Hassina; Ahmed, Yashi (2009) The adenomatous polyposis coli tumor suppressor and Wnt signaling in the regulation of apoptosis. Adv Exp Med Biol 656:75-84

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