Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.
复制标题
DOI：
10.1038/ncb1909
复制
发表时间：
2009-08
影响因子：
21.3
通讯作者：
Campisi, Judith
中科院分区：
文献类型：
--
作者：
Rodier, Francis;Coppe, Jean-Philippe;Patil, Christopher K.;Hoeijmakers, Wieteke A. M.;Munoz, Denise P.;Raza, Saba R.;Freund, Adam;Campeau, Eric;Davalos, Albert R.;Campisi, Judith
细胞衰老通过稳定地阻止受损细胞的增殖来抑制癌症。矛盾的是，衰老细胞也会分泌改变组织微环境的因子。调节这种分泌的途径尚不清楚。我们发现，受损的人类细胞会产生持续的染色质损伤，并伴有DNA双链断裂（DSBs）的特征，从而引发炎症细胞因子如白细胞介素-6 （IL-6）的分泌增加。细胞因子的分泌只发生在持续DNA损伤信号的建立之后，通常与衰老相关，而不是在短暂DNA损伤反应（DDR）之后。这种细胞因子反应的启动和维持需要DDR蛋白ATM、NBS1和CHK2，而不需要细胞周期阻滞执行者p53和pRb。在癌基因诱导的衰老和绕过衰老的受损细胞中，ATM对于IL-6的分泌也是必不可少的。此外，DDR活性和IL-6在人类癌症中升高，atm消耗抑制衰老细胞刺激IL-6依赖性癌细胞侵袭的能力。因此，除了协调细胞周期检查点和DNA修复外，DDR的一个新颖而重要的作用是允许受损细胞将其受损状态传达给周围组织。
Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
登录
查看更多内容
影响因子：
11.2
作者：
Bavik, C;Coleman, I;Nelson, PS
通讯作者：
Nelson, PS
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
14.9
作者：
Rodier, Francis;Campisi, Judith;Bhaumik, Dipa
通讯作者：
Bhaumik, Dipa