The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways
The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways
复制标题
DOI：
10.1074/jbc.m008527200
复制
发表时间：
2001-02-16
影响因子：
4.8
通讯作者：
Frisan, T
中科院分区：
文献类型：
--
作者：
Cortes-Bratti, X;Karlsson, C;Frisan, T
细胞致死扩张性毒素（CDTs）诱导细胞周期阻滞的机制尚不清楚。我们证明了杜克雷嗜血杆菌CDT （HdCDT）的作用是细胞类型特异性的：B细胞系发生凋亡，上皮细胞和角质形成细胞只在G(2)中被阻滞，而正常成纤维细胞在G(1)和G(2)中都被阻滞。我们研究了正常的角质形成细胞和成纤维细胞，这与了解杜氏弧菌的致病性有关。对HdCDT的反应类似于电离辐射激活的检查点反应。这两种反应的特征都是在成纤维细胞中早期诱导p53基因和细胞周期蛋白依赖性激酶抑制剂p21，以及在上皮细胞中激活chk2激酶。在Ataxia telansecasia突变基因（ATM）缺陷淋巴母细胞系中，与ATM野生型细胞相比，中毒明显延迟，并且与p53稳定的较慢动力学相关，这表明对HdCDT的早期反应依赖于ATM。咖啡因部分覆盖hdcdt介导的细胞周期阻滞的能力进一步证实了atm依赖通路的激活。我们的数据揭示了这种新型细菌毒素家族的作用机制，将目标候选物限制在直接参与激活检查点反应的DNA或分子上。
The cytolethal distending toxins (CDTs) induce cell cycle arrest by a mechanism still not well characterized. We demonstrate that the effect of the Haemophilus ducreyi CDT (HdCDT) is cell type-specific: B cell lines underwent apoptosis, epithelial cells and keratinocytes arrested exclusively in G(2), whereas normal fibroblasts arrested both in G(1) and G(2). We studied normal keratinocytes and fibroblasts, which are relevant for understanding the pathogenicity of H. ducreyi. The response to HdCDT resembles the checkpoint response activated by ionizing radiation. Both responses were characterized by an early induction of the p53 gene and the cyclin-dependent kinase inhibitor p21 in fibroblasts, and activation of the chk2 kinase in epithelial cells. In the Ataxia Telansectasia-mutated gene (ATM)-deficient lymphoblastoid cell lines, intoxication was significantly delayed compared with ATM wild type cells, and was associated with a slower kinetic of p53 stabilization, suggesting that the early response to HdCDT is ATM-dependent. Activation of ATM-dependent pathways was further confirmed by the ability of caffeine to partially override the HdCDT-mediated cell cycle arrest. Our data shed new light on the mechanism of action of this novel family of bacterial toxins, limiting the target candidates to DNA or molecules directly involved in activation of checkpoint responses.