Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence
Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence
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DOI：
10.1038/ncb1491
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发表时间：
2006-11-01
影响因子：
21.3
通讯作者：
Hara, Eiji
中科院分区：
文献类型：
--
作者：
Takahashi, Akiko;Ohtani, Naoko;Hara, Eiji
p16（INK 4a）细胞周期蛋白依赖性激酶抑制剂通过激活细胞衰老中的视网膜母细胞瘤（Rb）肿瘤抑制蛋白pRb（1-5）在建立稳定的G1细胞周期阻滞中具有关键作用。在这里，我们表明，p16（INK 4a）/Rb通路也与促有丝分裂信号合作，诱导细胞内活性氧（ROS）水平升高，从而激活蛋白激酶C δ（PKC δ）在人类衰老细胞。重要的是，一旦被ROS激活，PKC δ促进ROS的进一步产生，从而建立正反馈环以维持ROS-PKC δ信号传导（6-8）。ROS-PKC δ信号传导的持续激活不可逆地阻断胞质分裂，至少部分是通过降低人衰老细胞中胞质分裂所需的WARTS（也称为LATS 1），一种有丝分裂出口网络（MEN）激酶的水平（9- 11）。这种不可逆的细胞动力学阻滞可能作为细胞永生化的第二个屏障，确保人类衰老细胞中稳定的细胞周期停滞。这些结果揭示了p16（INK 4a）-Rb通路的一个意想不到的作用，并为人类细胞中衰老细胞周期阻滞是如何被强制执行的提供了新的见解。
The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb(1-5) in cellular senescence. Here, we show that the p16(INK4a)/Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase C delta (PKC delta) in human senescent cells. Importantly, once activated by ROS, PKC delta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKC delta signalling(6-8). Sustained activation of ROS-PKC delta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis(9--11), in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16(INK4a)-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.