Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, USA.
Cancer Cell. 2011 Jun 14;19(6):701-14. doi: 10.1016/j.ccr.2011.04.017.
Multiple mechanisms have been proposed to explain how Rb and p53 tumor suppressor loss lead to chromosome instability (CIN). It was recently shown that Rb pathway inhibition causes overexpression of the mitotic checkpoint gene Mad2, but whether Mad2 overexpression is required to generate CIN in this context is unknown. Here, we show that CIN in cultured cells lacking Rb family proteins requires Mad2 upregulation and that this upregulation is also necessary for CIN and tumor progression in vivo. Mad2 is also repressed by p53 and its upregulation is required for CIN in a p53 mutant tumor model. These results demonstrate that Mad2 overexpression is a critical mediator of the CIN observed upon inactivation of two major tumor suppressor pathways.
已经提出了多种机制来解释 Rb 和 p53 肿瘤抑制因子缺失如何导致染色体不稳定 (CIN)。最近表明，Rb 途径抑制导致有丝分裂检查点基因 Mad2 的过表达，但在这种情况下，Mad2 过表达是否是产生 CIN 的必要条件尚不清楚。在这里，我们表明，缺乏 Rb 家族蛋白的培养细胞中的 CIN 需要 Mad2 的上调，并且这种上调对于体内的 CIN 和肿瘤进展也是必需的。Mad2 也受到 p53 的抑制，其上调对于 p53 突变肿瘤模型中的 CIN 也是必需的。这些结果表明，Mad2 过表达是两种主要肿瘤抑制途径失活时观察到的 CIN 的关键介质。
