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Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Abstract

The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/β-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/β-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on β-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/β-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Acknowledgements

We are grateful to Dr Trevor Dale for donating HA-Dvl-2 (mouse) expression vector, Dr Akira Kikuchi for donating pCCN/Dvl-1 (human) and pEF-BOS-myc/Dvl-3 (human) plasmids, Dr Howe PH for donating pCDNA3-myc/Axin (human) and Dr Shinji Takada for donating mouse fibroblast L cells producing Wnt-3a and L cells stably transfected with the pGKneo plasmid. We thank Ivan Bièche and Christian Gespash for useful comments, Florence Copigny and Cédrick Lefol for excellent technical assistance, and Philippe Leclerc (IFR 93, kremelin Bicétre, France) for immunofluorescence analysis. This work was supported by a GenHomme Network Grant (02490-6088) to Hybrigenics and Institut Curie. We thank all the Hybrigenics staff for their contribution and the staff of the Drosoman laboratory, headed by Jacques Camonis and supported by Institut Curie.

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Correspondence to F Lallemand.

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Bouteille, N., Driouch, K., Hage, P. et al. Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein. Oncogene 28, 2569–2580 (2009). https://doi.org/10.1038/onc.2009.120

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