Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Mol Cell. 2014 Jul 3;55(1):73-84. doi: 10.1016/j.molcel.2014.05.003. Epub 2014 Jun 5.
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.
衰老（senescence）是一种永久性生长停滞的状态，也是体内抗肿瘤屏障的关键部分。尽管肿瘤抑制因子 p53 和 pRb 家族蛋白的活性对于诱导衰老至关重要，但这些蛋白诱导衰老的分子机制尚不清楚。通过延时活细胞成像，我们在此证明，暴露于各种衰老诱导刺激下的正常人二倍体成纤维细胞（HDF）在进入永久性细胞周期停滞之前会跳过一次有丝分裂。这种有丝分裂跳过是由 p53 依赖性 APC/C（Cdh1）过早激活和 pRb 家族蛋白依赖性有丝分裂调节因子转录抑制共同介导的。重要的是，有丝分裂跳过对于衰老的诱导是必需且充分的。p16 仅需要用于维持衰老。对人类痣的分析也表明了有丝分裂跳过在体内衰老中的作用。我们的发现为细胞衰老的诱导和维持提供了决定性的分子基础证据。
