Dai Wei, Wang Qi, Liu Tongyi, Swamy Malisetty, Fang Yuqiang, Xie Suqing, Mahmood Radma, Yang Yang-Ming, Xu Ming, Rao Chinthalapally V
Division of Molecular Carcinogenesis, Department of Medicine, New York Medical College, Valhalla, New York, USA.
Cancer Res. 2004 Jan 15;64(2):440-5. doi: 10.1158/0008-5472.can-03-3119.
A compromised spindle checkpoint is thought to play a key role in genetic instability that predisposes cells to malignant transformation. Loss of function mutations of BubR1, an important component of the spindle checkpoint, have been detected in human cancers. Here we show that BubR1(+/-) mouse embryonic fibroblasts are defective in spindle checkpoint activation, contain a significantly reduced amount of securin and Cdc20, and exhibit a greater level of micronuclei than do wild-type cells. RNA interference-mediated down-regulation of BubR1 also greatly reduced securin level. Moreover, compared with wild-type littermates, BubR1(+/-) mice rapidly develop lung as well as intestinal adenocarcinomas in response to challenge with carcinogen. BubR1 is thus essential for spindle checkpoint activation and tumor suppression.
纺锤体检查点功能受损被认为在遗传不稳定性中起关键作用，而遗传不稳定性会使细胞易于发生恶性转化。在人类癌症中已检测到纺锤体检查点的重要组成部分BubR1的功能丧失突变。在此我们表明，BubR1(+/-)小鼠胚胎成纤维细胞在纺锤体检查点激活方面存在缺陷，securin和Cdc20的含量显著降低，并且与野生型细胞相比，微核水平更高。RNA干扰介导的BubR1下调也大大降低了securin水平。此外，与野生型同窝小鼠相比，BubR1(+/-)小鼠在受到致癌物攻击后会迅速发展为肺癌和肠道腺癌。因此，BubR1对于纺锤体检查点激活和肿瘤抑制至关重要。
