Inactivation of hCDC4 can cause chromosomal instability
Inactivation of hCDC4 can cause chromosomal instability
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DOI：
10.1038/nature02313
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发表时间：
2004-03-04
期刊：
影响因子：
64.8
通讯作者：
Lengauer, C
中科院分区：
文献类型：
--
作者：
Rajagopalan, H;Jallepalli, PV;Lengauer, C
非整倍体是一种异常的染色体数量，近一个世纪以来一直被认为是人类癌症的标志(1)；然而，造成这种异常的机制仍然难以捉摸。在此，我们报告了人类结直肠癌及其前驱病变中 hCDC4（也称为 Fbw7 或 Archipelago）突变的鉴定。我们发现，通过靶向破坏核型稳定的结直肠癌细胞中的基因，使 hCDC4 基因失活，导致与微核和染色体不稳定相关的显着表型。这种表型可以追溯到中期执行和随后的染色体传递中的缺陷，并且依赖于细胞周期蛋白E-一种受hCDC4调节的蛋白（参考文献2-4）。我们的数据表明，染色体不稳定是由大部分人类癌症中的特定基因改变引起的，并且可能发生在恶性转化之前。
Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century(1); however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E-a protein that is regulated by hCDC4 (refs 2-4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion.