Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells.
Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells.
复制标题
DOI：
--
复制
发表时间：
2007
期刊：
影响因子：
8
通讯作者：
K. Aoki;M. Aoki;M. Sugai;N. Harada;H. Miyoshi;T. Tsukamoto;T. Mizoshita;M. Tatematsu;H. Seno;T. Chiba;M. Oshima;C. Hsieh;M. Taketo
中科院分区：
文献类型：
--
作者：
K. Aoki;M. Aoki;M. Sugai;N. Harada;H. Miyoshi;T. Tsukamoto;T. Mizoshita;M. Tatematsu;H. Seno;T. Chiba;M. Oshima;C. Hsieh;M. Taketo
大肠腺瘤性息肉病（APC/Apc）基因编码一个关键的肿瘤抑制因子，其突变激活β-连环蛋白/T细胞因子（TCF）介导的转录（经典Wnt信号传导）。在这里，我们表明Wnt信号可以导致染色体不稳定性（CIN）。作为CIN的指标，我们对小鼠息肉和ES细胞中的后期桥指数（ABI）进行了评分，其中Wnt信号转导被Apc或β-连环蛋白突变激活。我们发现ABI比野生型对照组高3到9倍。此外，核型分析证实，Wnt信号激活的ES细胞以更高的速率产生新的染色体畸变;因此CIN。一致地，在这些细胞中显性阴性TCF的表达降低了它们的ABI。我们还发现，Wnt信号激活增加了Cdc2（Cdk1）的磷酸化，抑制其活性，并抑制细胞暴露于诺考达唑或秋水仙胺后的凋亡。这些数据表明，Wnt信号刺激细胞逃避有丝分裂停滞和凋亡，导致CIN。在有核β-catenin表达的胃癌组织中，ABI显著高于无核β-catenin表达的胃癌组织。这些结果共同表明，β-连环蛋白/TCF介导的转录本身通过G2/M进展的失调增加CIN。
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.