The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors
The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors
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DOI：
10.1038/ncomms3880
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发表时间：
2013-12-01
影响因子：
16.6
通讯作者：
Malumbres, Marcos
中科院分区：
文献类型：
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作者：
Eguren, Manuel;Porlan, Eva;Malumbres, Marcos
E3-泛素连接酶APC/C-Cdh 1是核内复制所必需的，但其在哺乳动物有丝分裂细胞周期中的相关性仍不清楚。在这里，我们表明，基因消融Cdh 1在发育中的神经系统的结果在发育不良的大脑和脑积水。这些缺陷与Cdh 1底物水平的提高和神经祖细胞进入S期的增加相关。然而，细胞分裂被阻止在Cdh 1的情况下，由于过度激活的细胞周期蛋白依赖性激酶，复制应激，诱导p53，G2停滞和这些祖细胞的凋亡死亡。伴随消融p53挽救细胞凋亡，但不复制压力，导致整个成人大脑中受损的神经元的存在。这些数据表明，Cdh 1在体内的失活导致复制应激，细胞周期停滞和细胞死亡，支持最近的治疗建议，旨在抑制肿瘤中的APC/C。
The E3-ubiquitin ligase APC/C-Cdh1 is essential for endoreduplication but its relevance in the mammalian mitotic cell cycle is still unclear. Here we show that genetic ablation of Cdh1 in the developing nervous system results in hypoplastic brain and hydrocephalus. These defects correlate with enhanced levels of Cdh1 substrates and increased entry into the S phase in neural progenitors. However, cell division is prevented in the absence of Cdh1 due to hyperactivation of cyclin-dependent kinases, replicative stress, induction of p53, G2 arrest and apoptotic death of these progenitor cells. Concomitant ablation of p53 rescues apoptosis but not replicative stress, resulting in the presence of damaged neurons throughout the adult brain. These data indicate that the inactivation of Cdh1 in vivo results in replicative stress, cell cycle arrest and cell death, supporting recent therapeutic proposals aimed to inhibit the APC/C in tumours.