Mutations of mitotic checkpoint genes in human cancers
Mutations of mitotic checkpoint genes in human cancers
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DOI：
10.1038/32688
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发表时间：
1998-03-19
期刊：
影响因子：
64.8
通讯作者：
Vogelstein, B
中科院分区：
文献类型：
--
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
遗传不稳定性是最早被假定为肿瘤形成的特征之一(1-3)。这种遗传不稳定性以两种不同的形式出现。在一小部分结直肠癌和其他一些癌症中，不匹配碱基的修复缺陷会导致核苷酸水平突变率增加，从而导致广泛的微卫星不稳定(4-7)。在大多数结直肠癌以及许多其他癌症类型中，观察到导致染色体数量异常（非整倍性）的染色体不稳定性 (GIN) (8)。这种普遍异常的生理和分子基础尚不清楚。在这里，我们表明，CIN 始终与有丝分裂检查点功能的丧失相关。此外，在一些显示 CIN 的癌症中，该检查点的丧失与酵母 BUB1 基因的人类同源物的突变失活有关。 BUB1 控制酵母中有丝分裂检查点和染色体分离。表现出微卫星不稳定性的细胞的正常有丝分裂检查点在从两种 CIN 癌症中的任何一种转移突变 hBUB1 等位基因后变得有缺陷。
Genetic instability was one of the first characteristics to be postulated to underlie neoplasia(1-3). Such genetic instability occurs in two different forms. In a small fraction of colorectal and some other cancers, defective repair of mismatched bases results in an increased mutation rate at the nucleotide level and consequent widespread microsatellite instability(4-7). In most colorectal cancers, and probably in many other cancer types, a chromosomal instability (GIN) leading to an abnormal chromosome number (aneuploidy) is observed(8). The physiological and molecular bases of this pervasive abnormality are unknown. Here we show that CIN is consistently associated with the loss of function of a mitotic checkpoint, Moreover, in some cancers displaying CIN the loss of this checkpoint was associated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast, The normal mitotic checkpoints of cells displaying microsatellite instability become defective upon transfer of mutant hBUB1 alleles from either of two CIN cancers.