Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705, USA.
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):E2205-14. doi: 10.1073/pnas.1201911109. Epub 2012 Jul 9.
The mitotic checkpoint is the major cell cycle checkpoint acting during mitosis to prevent aneuploidy and chromosomal instability, which are hallmarks of tumor cells. Reduced expression of the mitotic checkpoint component Mad1 causes aneuploidy and promotes tumors in mice [Iwanaga Y, et al. (2007) Cancer Res 67:160-166]. However, the prevalence and consequences of Mad1 overexpression are currently unclear. Here we show that Mad1 is frequently overexpressed in human cancers and that Mad1 up-regulation is a marker of poor prognosis. Overexpression of Mad1 causes aneuploidy and chromosomal instability through weakening mitotic checkpoint signaling caused by mislocalization of the Mad1 binding partner Mad2. Cells overexpressing Mad1 are resistant to microtubule poisons, including currently used chemotherapeutic agents. These results suggest that levels of Mad1 must be tightly regulated to prevent aneuploidy and transformation and that Mad1 up-regulation may promote tumors and cause resistance to current therapies.
有丝分裂检查点是在有丝分裂期间起作用的主要细胞周期检查点，以防止非整倍体和染色体不稳定性，这是非整倍体肿瘤细胞的标志。有丝分裂检查点成分 Mad1 的表达减少会导致非整倍体并促进小鼠肿瘤的发生[Iwanaga Y，等（2007）癌症 Res 67：160-166]。然而，Mad1 过表达的流行率和后果目前尚不清楚。在这里，我们表明 Mad1 在人类癌症中经常过表达，并且 Mad1 的上调是预后不良的标志物。Mad1 的过表达通过 Mad1 结合伴侣 Mad2 的定位错误导致有丝分裂检查点信号减弱，导致非整倍体和染色体不稳定性。过表达 Mad1 的细胞对微管毒物有抗性，包括目前使用的化疗药物。这些结果表明，Mad1 的水平必须受到严格控制，以防止非整倍体和转化，并且 Mad1 的上调可能会促进肿瘤的发生并导致对当前治疗方法的耐药性。
