Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction
Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction
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DOI：
10.1016/j.molcel.2014.05.003
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发表时间：
2014-07-03
期刊：
影响因子：
16
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Johmura, Yoshikazu;Shimada, Midori;Nakanishi, Makoto
衰老是一种永久性生长停滞的状态，是体内抗肿瘤屏障的关键部分。虽然p53和pRb家族蛋白的肿瘤抑制活性对于诱导衰老是必不可少的，但是这些蛋白诱导衰老的分子机制仍然不清楚。使用延时活细胞成像，我们在这里证明，正常的人二倍体成纤维细胞（HDF）暴露于各种衰老诱导刺激进行有丝分裂跳跃进入永久性细胞周期停滞之前。这种有丝分裂跳跃由APC/C-Cdh 1的p53依赖性过早激活和有丝分裂调节因子的pRb家族蛋白依赖性转录抑制介导。重要的是，有丝分裂跳跃对于衰老诱导是必要和充分的。p16仅用于维持衰老。对人类痣的分析也表明有丝分裂跳跃在体内衰老中的作用。我们的研究结果为细胞衰老的诱导和维持的分子基础提供了决定性的证据。
Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell-cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/C-Cdh1 and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. p16 is only required for maintenance of senescence. Analysis of human nevi also suggested the role of mitosis skip in in vivo senescence. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.