IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'.
IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'.
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DOI：
10.18632/aging.100520
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Hodny Z
中科院分区：
文献类型：
--
作者：
Hubackova S;Krejcikova K;Bartek J;Hodny Z
许多癌症发生在感染和炎症部位。细胞衰老是一种细胞周期停滞的永久状态，为肿瘤发生提供了屏障，伴随着促炎细胞因子如IL 1、IL 6、IL 8和TNFα的升高。在这里，我们证明了由经历任何三种主要形式的衰老，即复制，癌基因和药物诱导的细胞条件培养基，含有高水平的IL 1，IL 6和TGF β能够诱导活性氧（ROS）介导的DNA损伤反应（DDR）。持续的细胞因子信号和激活的DDR引起正常旁观者细胞的衰老，伴随着JAK/STAT、TGFβ/SMAD和IL 1/NFκB信号通路的激活。抑制IL 6/STAT信号通路对旁观者细胞DDR诱导无影响，而抑制TGFβ/SMAD或IL 1/NFκB通路则导致旁观者细胞ROS产生减少和DDR减少。同时抑制TGFβ/SMAD和IL 1/NFκB通路完全抑制DDR，表明IL 1和TGFβ协同诱导和/或维持旁观者衰老。此外，观察到的IL 1和TGFβ诱导的NAPDH氧化酶Nox 4表达表明衰老相关分泌表型（SASP）和DNA损伤信号传导之间的机制联系，这是所有主要形式的旁分泌旁观者衰老发展所共有的特征。
Many cancers arise at sites of infection and inflammation. Cellular senescence, a permanent state of cell cycle arrest that provides a barrier against tumorigenesis, is accompanied by elevated proinflammatory cytokines such as IL1, IL6, IL8 and TNFα. Here we demonstrate that media conditioned by cells undergoing any of the three main forms of senescence, i.e. replicative, oncogene- and drug-induced, contain high levels of IL1, IL6, and TGFb capable of inducing reactive oxygen species (ROS)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGFβ/SMAD and IL1/NFκB signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFβ/SMAD or IL1/NFκB pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGFβ/SMAD and IL1/NFκB pathways completely suppressed DDR indicating that IL1 and TGFβ cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGFβ-induced expression of NAPDH oxidase Nox4 indicates a mechanistic link between the senescence-associated secretory phenotype (SASP) and DNA damage signaling as a feature shared by development of all major forms of paracrine bystander senescence.
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临时细胞性白血病核体的行为是DNA损伤传感器，其对DNA双链断裂的反应由NBS1和激酶ATM，CHK2和ATR调节。
DOI：
10.1083/jcb.200604009
发表时间：
2006-10-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dellaire G;Ching RW;Ahmed K;Jalali F;Tse KC;Bristow RG;Bazett-Jones DP
通讯作者：
Bazett-Jones DP
DOI：
10.18632/aging.100281
发表时间：
2011-02
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
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：
11.2
作者：
Bavik, C;Coleman, I;Nelson, PS
通讯作者：
Nelson, PS
影响因子：
8
作者：
Carbone, R;Pearson, M;Pelicci, PG
通讯作者：
Pelicci, PG