Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas
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Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. / Koch, Arend; Hrychyk, Aksana; Hartmann, Wolfgang; Waha, Anke; Mikeska, Thomas; Waha, Andreas; Schüller, Ulrich; Sörensen, Nils; Berthold, Frank; Goodyer, Cynthia G; Wiestler, Otmar D; Birchmeier, Walter; Behrens, Jürgen; Pietsch, Torsten.
In: INT J CANCER, Vol. 121, No. 2, 15.07.2007, p. 284-91.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas
AU - Koch, Arend
AU - Hrychyk, Aksana
AU - Hartmann, Wolfgang
AU - Waha, Anke
AU - Mikeska, Thomas
AU - Waha, Andreas
AU - Schüller, Ulrich
AU - Sörensen, Nils
AU - Berthold, Frank
AU - Goodyer, Cynthia G
AU - Wiestler, Otmar D
AU - Birchmeier, Walter
AU - Behrens, Jürgen
AU - Pietsch, Torsten
N1 - (c) 2007 Wiley-Liss, Inc.
PY - 2007/7/15
Y1 - 2007/7/15
N2 - Medulloblastomas (MBs) represent the most common malignant brain tumors in children. Most MBs develop sporadically in the cerebellum, but their incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations in the APC tumor suppressor gene. APC is part of a multiprotein complex involved in the Wnt signaling pathway that controls the stability of beta-catenin, the central effector in this cascade. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin and its partners, APC and AXIN1, which cause activation of Wnt signaling. The pathway is negatively controlled by the tumor suppressor AXIN2 (Conductin), a scaffold protein of this signaling complex. To investigate whether alterations in AXIN2 may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the AXIN2 gene in 116 MB biopsy samples and 11 MB cell lines using single-strand conformation polymorphism and sequencing analysis. One MB displayed a somatic, tumor-specific 2 bp insertion in exon 5, leading to carboxy-terminal truncation of the AXIN2 protein. This tumor biopsy showed nuclear accumulation of beta-catenin protein, indicating an activation of Wnt signaling. In 2 further MB biopsies, mutations were identified in exon 5 (Glu408Lys) and exon 8 (Ser738Phe) of the AXIN2 gene, which are due to predicted germline mutations and rare polymorphisms. mRNA expression analysis in 22 MBs revealed reduced expression of AXIN2 mRNA compared to 8 fetal cerebellar tissues. Promoter hypermethylation could be ruled out as a major cause for transcriptional silencing by bisulfite sequencing. To study the functional role of AXIN2 in MBs, wild-type AXIN2 was overexpressed in MB cell lines in which the Wnt signaling pathway was activated by Wnt-3a. In this assay, AXIN2 inhibited Wnt signaling demonstrated in luciferase reporter assays. In contrast, overexpression of mutated AXIN2 with a deleted C-terminal DIX-domain resulted in an activation of the Wnt signaling pathway. These findings indicate that mutations of AXIN2 can lead to an oncogenic activation of the Wnt pathway in MBs.
AB - Medulloblastomas (MBs) represent the most common malignant brain tumors in children. Most MBs develop sporadically in the cerebellum, but their incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations in the APC tumor suppressor gene. APC is part of a multiprotein complex involved in the Wnt signaling pathway that controls the stability of beta-catenin, the central effector in this cascade. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin and its partners, APC and AXIN1, which cause activation of Wnt signaling. The pathway is negatively controlled by the tumor suppressor AXIN2 (Conductin), a scaffold protein of this signaling complex. To investigate whether alterations in AXIN2 may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the AXIN2 gene in 116 MB biopsy samples and 11 MB cell lines using single-strand conformation polymorphism and sequencing analysis. One MB displayed a somatic, tumor-specific 2 bp insertion in exon 5, leading to carboxy-terminal truncation of the AXIN2 protein. This tumor biopsy showed nuclear accumulation of beta-catenin protein, indicating an activation of Wnt signaling. In 2 further MB biopsies, mutations were identified in exon 5 (Glu408Lys) and exon 8 (Ser738Phe) of the AXIN2 gene, which are due to predicted germline mutations and rare polymorphisms. mRNA expression analysis in 22 MBs revealed reduced expression of AXIN2 mRNA compared to 8 fetal cerebellar tissues. Promoter hypermethylation could be ruled out as a major cause for transcriptional silencing by bisulfite sequencing. To study the functional role of AXIN2 in MBs, wild-type AXIN2 was overexpressed in MB cell lines in which the Wnt signaling pathway was activated by Wnt-3a. In this assay, AXIN2 inhibited Wnt signaling demonstrated in luciferase reporter assays. In contrast, overexpression of mutated AXIN2 with a deleted C-terminal DIX-domain resulted in an activation of the Wnt signaling pathway. These findings indicate that mutations of AXIN2 can lead to an oncogenic activation of the Wnt pathway in MBs.
KW - Adolescent
KW - Adult
KW - Axin Protein
KW - Base Sequence
KW - Blotting, Western
KW - Cell Line, Tumor
KW - Cerebellum
KW - Child
KW - Child, Preschool
KW - Cytoskeletal Proteins
KW - DNA Methylation
KW - DNA Mutational Analysis
KW - Female
KW - Gene Expression Profiling
KW - Humans
KW - Infant
KW - Male
KW - Medulloblastoma
KW - Middle Aged
KW - Mutation
KW - RNA, Messenger
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - TCF Transcription Factors
KW - Transcription, Genetic
KW - Wnt1 Protein
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1002/ijc.22675
DO - 10.1002/ijc.22675
M3 - SCORING: Journal article
C2 - 17373666
VL - 121
SP - 284
EP - 291
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 2
ER -