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Our research uses Drosophila as a model to study the evolutionarily conserved Wnt/Wingless signal transduction pathway, with a focus on one component in this pathway, Adenomatous polyposis coli (APC). Wnt/Wingless signaling directs cell proliferation, cell fate, and apoptotic cell death during development and is inappropriately activated in several types of cancer. The majority of colorectal carcinomas have truncating mutations in APC, a negative regulator in Wnt signaling. APC functions in a protein complex that targets the key transcriptional activator in the pathway, beta-catenin, for proteasomal degradation. Thus inactivation of APC results in ectopic Wnt signaling, and the aberrant activation of target genes. The primary goals of our research are to determine the molecular mechanisms by which APC regulates Wnt signaling, and the molecular consequences of APC loss.

 

Characterization of New Components in the Wingless Signaling Pathway

 

We have performed genetic modifier screens to identify new components that are required to promote Wingless signal transduction. These screens are based on the sensitive Apc1 mutant retinal apoptosis phenotype (shown above), which results from the constitutive activation of Wingless signaling. We have isolated mutations in genes that suppress this phenotype, and in this way have identified several candidate effector proteins.  Our current work is directed toward characterizing these novel genes, and determining their role in Wingless signaling. Given the evolutionary conservation of the Wnt/Wingless pathway, our hope is that these studies in Drosophila will extend current models for Wnt signal transduction, and may also inform our understanding of disease processes that are caused by inactivation of APC in humans.

 

Dissecting the Roles of Apc in Wingless Signaling

 

We are also investigating the roles of Apc in Wingless signal transduction. Two APC homologs exist in humans, mice, and fruit flies. We have used genetic techniques to inactivate both Drosophila homologs of Apc and these studies have revealed that the negative regulatory role of APC in Wnt signaling is conserved from flies to mammals. However, the exact molecular mechanisms by which APC regulates Wnt/Wingless signaling have remained elusive. Our current work is directed toward dissecting the roles of Apc in Wingless signaling, using genetic, biochemical, and cell biological methods.

 

 
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Genetics Department

MCB Graduate Program