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Wnt signalling and cancer

Mariann Bienz

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Medical Research Council (MRC)
The Wnt/beta-catenin signalling pathway is ancient and plays a key role during the normal development and tissue homeostasis of animals. This pathway is often dysregulated in human cancer. In particular, most colorectal cancers are due to hyperactive beta-catenin signalling in the intestinal epithelium, caused by mutational inactivation of its negative regulator, the Adenomatous polyposis Coli (APC) tumour suppressor, or by mutational activation of beta-catenin itself. Our aim is to understand the molecular and cell-biological mechanisms underlying the transduction of the Wnt signal from the plasma membrane to the nucleus in normal and malignant cells. In focus are the molecular functions of positive regulators of the Wnt pathway that have potential as drug targets, including Dishevelled and the Pygo-BCL9 complex. Our main questions are how Dishevelled assembles Wnt signalosomes to inactivate the Axin-APC complex, and how the Pygo-BCL9 complex enables the Wnt enhanceosome to activate beta-catenin-mediated transcription. Our approach is to combine biochemical, biophysical and structural analysis of these proteins with cell-biological analysis and functional assays in mammalian cell lines (including colorectal cancer cells) and in whole-organism models such as Drosophila and mice. We have also been awarded a CRUK programme grant to develop the potential of these Wnt signalling components as drug targets and to examine their regulation by the ubiquitin system.

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