Chi Ya-Hui, Ward Jerrold M, Cheng Lily I, Yasunaga Junichiro, Jeang Kuan-Teh
Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Int J Cancer. 2009 Mar 15;124(6):1483-9. doi: 10.1002/ijc.24094.
The spindle assembly checkpoint (SAC) guards against chromosomal missegregation during mitosis. To investigate the role of SAC in tumor development, mice heterozygously knocked out for the mitotic arrest deficient (Mad) genes Mad1 and/or Mad2 were mated with p53(+/) (-) mice. Increased tumor frequencies were reproducibly observed in Mad2(+/) (-)p53(+/) (-) (88.2%) and Mad1(+/) (-)Mad2(+/) (-)p53(+/) (-) (95.0%) mice compared with p53(+/) (-) (66.7%) mice. Moreover, 53% of Mad2(+/) (-)p53(+/) (-) mice developed lymphomas compared with 11% of p53(+/) (-) mice. By examining chromosome content, increased loss in diploidy was seen in cells from Mad2(+/) (-)p53(+/) (-) versus p53(+/) (-) mice, correlating loss of SAC function, in a p53(+/) (-) context, with increased aneuploidy and tumorigenesis. The findings here provide evidence for a cooperative role of Mad1/Mad2 and p53 genes in preventing tumor development.
纺锤体组装检查点（SAC）可防止有丝分裂期间染色体错分离。为了研究SAC在肿瘤发生中的作用，将有丝分裂阻滞缺陷（Mad）基因Mad1和/或Mad2杂合敲除的小鼠与p53(+/) (-)小鼠进行交配。与p53(+/) (-)（66.7%）小鼠相比，在Mad2(+/) (-)p53(+/) (-)（88.2%）和Mad1(+/) (-)Mad2(+/) (-)p53(+/) (-)（95.0%）小鼠中可重复性地观察到肿瘤发生率增加。此外，53%的Mad2(+/) (-)p53(+/) (-)小鼠发生淋巴瘤，而p53(+/) (-)小鼠的这一比例为11%。通过检查染色体含量，与p53(+/) (-)小鼠相比，Mad2(+/) (-)p53(+/) (-)小鼠细胞中观察到二倍体丢失增加，这表明在p53(+/) (-)背景下，SAC功能丧失与非整倍体增加和肿瘤发生相关。此处的研究结果为Mad1/Mad2和p53基因在预防肿瘤发生中的协同作用提供了证据。
