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

Abstract

Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate b-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 b-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signalactivated 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 b-catenin, ABI was significantly higher than in those without. These results collectively indicate that b-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

Wnt signaling and gastrointestinal tumorigenesis in mouse models

“…We have recently found significantly high anaphase bridge index (ABI), a marker of CIN, in the intestinal polyp epithelium and ES cells mutated in Apc or b-catenin gene. Importantly, such high ABI were reversed when the cells were introduced with dominant-negative TCF constructs, indicating that transcriptional activation was responsible (Aoki et al, 2006). Consistent with our observation, it has been shown that Wnt signaling causes CIN via upregulation of conductin (axin2) (Hadjihannas et al, 2006).…”

Interaction between Tumor Suppressor Adenomatous Polyposis Coli and Topoisomerase IIα: Implication for the G2/M Transition

“…Activated Wnt signaling resulting from stabilized ␤-catenin was recently reported to contribute to chromosome instability (Aoki et al, 2007) and lead to G2 arrest (Olmeda et al, 2003). Thus, we predicted that the abnormal nuclear morphology seen in cells expressing M2-APC was dependent on M2-APC association with and stabilization of nuclear ␤-catenin.…”

Mechanical factors activateß‐catenin‐dependent oncogene expression in APC1638N/+mouse colon

“…In addition, it has been shown in vivo that mechanical irritation of the epithelium can lead to an increased mutation rate (Takahashi et al, 2000). This suggests that cells of the APC deficient colon, which can already experience chromosomal missegregation due to dominant negative effects of truncated APC protein or insufficient full length APC during mitosis (Fodde et al, 2001;Tighe et al, 2004;Aoki et al, 2007;Draviam et al, 2006), may be exposed to an alternative route to loss of heterozygosity when subjected to mechanical stress, in addition to the effects demonstrated here on tumor gene expression in the haploinsufficient tissue.…”