Article

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

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Oncogene (impact factor: 6.37). 06/2007; 26(24):3511-20. DOI:10.1038/sj.onc.1210141 pp.3511-20
Source: PubMed

ABSTRACT Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate beta-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 beta-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 beta-catenin, ABI was significantly higher than in those without. These results collectively indicate that beta-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Keywords

Adenomatous polyposis coli
 
anaphase bridge index
 
APC/Apc
 
apoptosis
 
canonical Wnt signaling
 
ES cells
 
G2/M progression
 
higher rates
 
human gastric cancer tissues
 
key tumor suppressor
 
mitotic arrest
 
mutations activate beta-catenin/T-cell factor
 
new chromosomal aberrations
 
suppressed apoptosis
 
times higher ABI
 
wild-type controls
 
Wnt signal activation
 
Wnt signal-activated ES cells
 
Wnt signaling
 
Wnt signaling stimulates