Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition.
Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition.
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DOI：
10.1016/j.ccr.2011.04.017
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发表时间：
2011-06-14
期刊：
影响因子：
50.3
通讯作者：
Benezra R
中科院分区：
文献类型：
--
作者：
Schvartzman JM;Duijf PH;Sotillo R;Coker C;Benezra R
多种机制已被提出来解释如何Rb和p53肿瘤抑制基因的丢失导致染色体不稳定性（CIN）。最近显示Rb途径抑制导致有丝分裂检查点基因Mad2的过表达，但在这种情况下是否需要Mad2过表达来产生CIN尚不清楚。在这里，我们表明，在培养的细胞缺乏Rb家族蛋白的CIN需要Mad2上调，这种上调也是必要的CIN和肿瘤的进展在体内。Mad2也被p53抑制，并且其上调是p53突变肿瘤模型中CIN所需的。这些结果表明，Mad2过表达是在两个主要肿瘤抑制途径失活后观察到的CIN的关键介质。染色体不稳定性（CIN）被认为是肿瘤进展的主要进化驱动力。在这里，我们表明，有丝分裂检查点基因Mad2的过度表达是所需的Rb和p53途径，两个途径经常在人类癌症中失活的抑制后观察到的CIN。我们的研究结果表明，CIN的获得是通过有丝分裂检查点途径的过度激活而导致主要肿瘤抑制途径的丢失。在癌症进展的早期阶段抑制这些肿瘤抑制途径可能是在没有其他遗传事件的情况下肿瘤中广泛存在CIN的原因，并强调了靶向非整倍体细胞的治疗价值。
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. Chromosome instability (CIN) is thought to be the major evolutionary driving force for tumor progression. Here we show that overexpression of the mitotic checkpoint gene Mad2 is required for the CIN observed upon inhibition of the Rb and p53 pathways, two pathways frequently inactivated in human cancer. Our results demonstrate that acquisition of CIN is hard-wired into loss of the major tumor suppressor pathways via hyperactivation of the mitotic checkpoint pathway. The inhibition of these tumor suppressor pathways in the early stages of cancer progression may account for the widespread presence of CIN in tumors in the absence of other genetic events and underscores the therapeutic value of targeting aneuploid cells.
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