Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a
Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a
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DOI：
10.1016/s1097-2765(04)00256-4
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发表时间：
2004-05-21
期刊：
影响因子：
16
通讯作者：
Sedivy, JM
中科院分区：
文献类型：
--
作者：
Herbig, U;Jobling, WA;Sedivy, JM
细胞衰老可以由端粒缩短以及各种压力和信号失衡引发。我们使用多参数单细胞检测方法来研究人成纤维细胞中的上游信号通路和随后的细胞周期检查点反应。含有多种DNA损伤反应因子的端粒灶在衰老细胞亚群中组装，并通过ATM向p53发出信号，上调p21并引起G1期阻滞。ATM表达或活性的抑制导致细胞周期重新进入，表明稳定的停滞需要持续的信号传导。ATR激酶似乎在正常细胞中起次要作用，但在ATM的情况下引起延迟的G2期阻滞。这些途径不影响p16的表达，p16在一个细胞亚群中以端粒和DNA损伤独立的方式上调。因此，不同的衰老程序可以并行进行，从而产生马赛克培养物以及对多种信号做出反应的单个细胞。
Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals.