Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling.
Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling.
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DOI：
10.1111/j.1582-4934.2009.00862.x
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发表时间：
2010-01
影响因子：
5.3
通讯作者：
Bartek J
中科院分区：
文献类型：
--
作者：
Blazkova H;Krejcikova K;Moudry P;Frisan T;Hodny Z;Bartek J
细胞致死膨胀毒素（CDTs）是由革兰氏阴性菌兼性致病菌株产生和分泌的具有潜在遗传毒性作用的蛋白质。暴露于CDTs的哺乳动物细胞经历细胞类型依赖性细胞周期停滞或凋亡;然而，对这种中毒的细胞命运反应在机制上还不完全清楚。在这里，我们表明，正常细胞和癌细胞（BJ，IMR-90和WI-38成纤维细胞，HeLa和U2-OS细胞系），存活的杜克雷嗜血杆菌CDT中毒的急性期具有细胞衰老的标志。这种特征性表型包括持续激活的DNA损伤信号传导（检测为53BP1/γ H2AX+灶）、衰老相关β-半乳糖苷酶活性增强、早幼粒细胞白血病核区室扩增和诱导几种细胞因子（特别是白细胞介素IL-6、IL-8和IL-24）表达，这些都是经历复制性或过早细胞衰老的细胞所共有的总体特征。我们得出结论，类似于致癌，氧化和复制应力，细菌中毒的另一种病理生理刺激，诱导早衰，内在的细胞反应，可能是机械基础的'膨胀'形态诱发的CDTs。最后，两种抗癌屏障（细胞凋亡和细胞衰老）的激活，以及本文报告的染色体畸变（微核）证据，支持这组细菌毒素新出现的遗传毒性和潜在致癌作用，并保证进一步研究其在人类疾病中的作用。
Cytolethal distending toxins (CDTs) are proteins produced and secreted by facultative pathogenic strains of Gram-negative bacteria with potentially genotoxic effects. Mammalian cells exposed to CDTs undergo cell type-dependent cell-cycle arrest or apoptosis; however, the cell fate responses to such intoxication are mechanistically incompletely understood. Here we show that both normal and cancer cells (BJ, IMR-90 and WI-38 fibroblasts, HeLa and U2-OS cell lines) that survive the acute phase of intoxication by Haemophilus ducreyi CDT possess the hallmarks of cellular senescence. This characteristic phenotype included persistently activated DNA damage signalling (detected as 53BP1/γH2AX+ foci), enhanced senescence-associated β-galactosidase activity, expansion of promyelocytic leukaemia nuclear compartments and induced expression of several cytokines (especially interleukins IL-6, IL-8 and IL-24), overall features shared by cells undergoing replicative or premature cellular senescence. We conclude that analogous to oncogenic, oxidative and replicative stresses, bacterial intoxication represents another pathophysiological stimulus that induces premature senescence, an intrinsic cellular response that may mechanistically underlie the ‘distended’ morphology evoked by CDTs. Finally, the activation of the two anticancer barriers, apoptosis and cellular senescence, together with evidence of chromosomal aberrations (micronucleation) reported here, support the emerging genotoxic and potentially oncogenic effects of this group of bacterial toxins, and warrant further investigation of their role(s) in human disease.
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影响因子：
4.8
作者：
Cortes-Bratti, X;Karlsson, C;Frisan, T
通讯作者：
Frisan, T
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
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J