title: Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling.
abstract: Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-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 beta-catenin, export it from the nucleus, and thereby repress beta-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 beta-catenin, and cannot inhibit beta-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.
authors.affiliation: The Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Todd G
authors.initials: TG
authors.lastname: Mainprize
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Brandon
authors.initials: B
authors.lastname: Wainwright
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008527:Medulloblastoma / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C509239:SHH protein, human; C490764:SUFU protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin