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Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Oncogene volume 23, pages 4577–4583 (2004)Cite this article

Abstract

Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, β-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind β-catenin, export it from the nucleus, and thereby repress β-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of β-catenin, and cannot inhibit β-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.

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Acknowledgements

MDT and TGM were supported by a fellowship from the Neurosurgery Research Education Foundation for this work. JTR is a career scientist of the CIHR. This work was completed with funds from the National Cancer Institute of Canada, Brainchild, the Wiley and Laurie Berman Fund for Brain Tumor Research.

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Authors and Affiliations

  1. The Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Michael D Taylor, Todd G Mainprize & James T Rutka

  2. Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, Toronto, Ontario, Canada

    Michael D Taylor, Todd G Mainprize & James T Rutka

  3. Division of Molecular and Medical Genetics, University of Toronto, Toronto, Canada

    Xiaoyun Zhang, Chi-Chung Hui & Stephen W Scherer

  4. Clinical Science, University of Toronto, Toronto, Canada

    Ling Liu & David Hogg

  5. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    David Hogg

  6. Department of Medicine, University of Toronto, Toronto, Canada

    David Hogg

  7. Ritchie Research Laboratories, The University of Queensland, St Lucia, Qld., 4072, Australia

    Brandon Wainwright

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Correspondence to James T Rutka.

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Taylor, M., Zhang, X., Liu, L. et al. Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling. Oncogene 23, 4577–4583 (2004). https://doi.org/10.1038/sj.onc.1207605

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  • DOI: https://doi.org/10.1038/sj.onc.1207605

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