Mutations in the APC tumour suppressor gene cause chromosomal instability
Mutations in the APC tumour suppressor gene cause chromosomal instability
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DOI：
10.1038/35070129
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发表时间：
2001-04-01
影响因子：
21.3
通讯作者：
Clevers, H
中科院分区：
文献类型：
--
作者：
Fodde, R;Kuipers, J;Clevers, H
在结直肠癌中描述了两种形式的遗传不稳定性：微卫星不稳定性和染色体不稳定性。微卫星不稳定性是由错配修复基因突变引起的;染色体不稳定性是许多结直肠癌的标志，尽管在分子水平上还没有完全理解。由于在大多数结直肠肿瘤中发现了结肠腺瘤性息肉病（APC）基因的截短，我们认为APC的突变可能是染色体不稳定的原因。为了验证这一假设，我们检测了Min（多发性肠肿瘤）或Apc 1638 T等位基因纯合的小鼠胚胎干（ES）细胞。在这里，我们发现Ape突变ES细胞显示出广泛的染色体和纺锤体畸变，为APC在染色体分离中的作用提供了遗传证据。与此相一致的是，APC在有丝分裂期间在动粒处积累，Ape突变体细胞形成具有大量微管的有丝分裂纺锤体，所述微管与动粒无效地连接。在微卫星不稳定的结直肠癌细胞中，APC的253个氨基酸的羧基末端片段的诱导表达再现了这种表型。我们得出结论，位于β-连环蛋白调节结构域C-末端的APC序列的缺失有助于结直肠癌中的染色体不稳定性。
Two forms of genetic instability have been described in colorectal cancer(1): microsatellite instability and chromosomal instability. Microsatellite instability results from mutations in mismatch repair genes; chromosomal instability is the hallmark of many colorectal cancers, although it is not completely understood at the molecular level. As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability. To test this hypothesis, we examined mouse embryonic stem (ES) cells homozygous for Min (multiple intestinal neoplasia) or Apc1638T alleles, Here we show that Ape mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation. Consistent with this, APC accumulates at the kinetochore during mitosis, Ape mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulated by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells, We conclude that loss of APC sequences that lie C-terminal to the beta -catenin regulatory domain contributes to chromosomal instability in colorectal cancer.