Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

K. Aoki, M. Aoki, M. Sugai, N. Harada, H. Miyoshi, T. Tsukamoto, T. Mizoshita, M. Tatematsu, H. Seno, T. Chiba, M. Oshima, C. L. Hsieh, M. M. Taketo

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58 Citations (Scopus)

Abstract

Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate β-catenin/T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or β-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signal-activated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear β-catenin, ABI was significantly higher than in those without. These results collectively indicate that β-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

Original languageEnglish
Pages (from-to)3511-3520
Number of pages10
JournalOncogene
Volume26
Issue number24
DOIs
Publication statusPublished - 24-05-2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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