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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl.
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Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl.

机译：细胞粘附对DNA损伤诱导的细胞凋亡的调控独立于p53和c-Abl。

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摘要

Conventional cancer therapies are based on preferential killing of tumor cells by DNA damage. Previous work showed that, for certain cell types, loss of integrin-mediated adhesion decreased the apoptotic response to DNA damage because of decreased p53 levels after detachment from the extracellular matrix. Integrin ligation restored p53 and sensitivity to DNA damage. In this study, we show that c-Abl mediates a second pathway by which adhesion to extracellular matrix regulates cell killing by chemotherapeutic agents 5-arabinofuranosylcytosine, cisplatin, and camptothecin. Activation of c-Abl tyrosine kinase by DNA damage requires cell adhesion. Abl-dependent stabilization of p73, a p53-related proapoptotic transcription factor, is also adhesion-dependent. Sensitivity to the Abl inhibitor STI571 suggests differential utilization of the p53 and c-Abl/p73 pathways by different tumor cell lines. These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl/p73 pathway.
机译：常规的癌症疗法基于通过DNA损伤优先杀死肿瘤细胞。先前的工作表明，对于某些细胞类型，由于从细胞外基质脱离后p53水平降低，整合素介导的粘附力的丧失降低了对DNA损伤的凋亡反应。整联蛋白连接恢复了p53和对DNA损伤的敏感性。在这项研究中，我们显示c-Abl介导第二条途径，通过该途径粘附至细胞外基质可调节化疗药物5-阿拉伯呋喃糖基胞嘧啶，顺铂和喜树碱对细胞的杀伤力。 DNA损伤激活c-Abl酪氨酸激酶需要细胞粘附。 p73，p53相关的细胞凋亡转录因子，p73的abl依赖稳定化也依赖于粘附。对Abl抑制剂STI571的敏感性表明不同肿瘤细胞系对p53和c-Abl / p73途径的利用不同。这些数据表明，通过整合素连接激活替代性的c-Abl / p73途径，化学疗法杀死p53阴性肿瘤细胞将得到增强。

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