Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells.
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.
Aoki
K
K
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Aoki
M
M
Sugai
M
M
Harada
N
N
Miyoshi
H
H
Tsukamoto
T
T
Mizoshita
T
T
Tatematsu
M
M
Seno
H
H
Chiba
T
T
Oshima
M
M
Hsieh
C-L
CL
Taketo
M M
MM
D000236:Adenoma / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells; D016195:G2 Phase / Q000235:genetics; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics; D007417:Intestinal Polyps / Q000235:genetics; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin