Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

中文翻译：

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p21 和活性氧产生之间的反馈是细胞衰老所必需的。

细胞衰老 - 正常增殖细胞（如成纤维细胞）中循环的永久停滞 - 导致与年龄相关的哺乳动物组织稳态丧失，并充当肿瘤抑制机制。事实证明，导致衰老的途径比以前设想的更为复杂。结合计算机内相互作用组分析和功能性靶基因抑制、随机建模和活细胞显微镜，我们在这里表明存在一个由 DNA 损伤反应 (DDR) 触发的动态反馈回路，并且在延迟几天后，将细胞锁定在积极维持的“深度”细胞衰老状态。该循环的基本特征是检查点基因 CDKN1A (p21) 的长期激活通过 GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta 的串行信号传导诱导线粒体功能障碍和活性氧 (ROS) 的产生。这些 ROS 反过来补充短暂的 DNA 损伤病灶并维持持续的 DDR。我们表明，在建立衰老表型期间，该循环对于生长停滞的稳定性是必要的和充分的。