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首页> 外文期刊>Cytokine >Cellular cytokine receptor signaling and ATM pathway intersections affect hepatic DNA repair
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Cellular cytokine receptor signaling and ATM pathway intersections affect hepatic DNA repair

机译：细胞细胞因子受体信号和ATM途径交叉口影响肝脏DNA修复

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Pathways involving ataxia telangiectasia mutated (ATM) gene and its downstream partners and effectors are critical for the DNA damage response. Cell survival, proliferation and tissue homeostasis are dependent upon preservation of DNA integrity but additional intracellular mechanisms contribute in these processes. As receptor-mediated signaling with beneficial intersections in ATM pathways could have therapeutic significance, we interrogated such intersections with assays using HuH-7 cells (hepatocytes). These cells were subjected to acetaminophen toxicity, which is a leading cause of hepatic injury and acute liver failure in people. The ATM pathway was examined in HuH-7-ATM-Prom-tdT cells containing fluorescent td-Tomato transgene reporter for ATM promoter activity. Titrated doses of specific growth factors were used as ligands for receptor-mediated signaling. The contribution of JAK/STAT3 signaling was defined by the loss-of-function approach with the JAK antagonist, ruxolitinib. In these assays, impairment in ATM-related DNA damage response following acetaminophen toxicity was ameliorated by selected growth factors, including fibroblast growth factors, granulocyte colony stimulating factor and vascular endothelial growth factor. The JAK/STAT3 signaling was exclusive to granulocyte colony stimulating factor but concerned additional pathways in cases of other growth factors. Antagonism of JAK/STAT3 by ruxolitinib abrogated benefits in ATM pathway-mediated DNA repair; and identification of the ruxolitinib-sensitive component of cytoprotection allowed separations of these pathway intersections. Therefore, this subtractive approach for ATM and other regulators in pathways will be informative for DNA damage response. These mechanisms will benefit therapeutic development for ATM-related tissue and organ injuries.
机译：涉及Ataxia Telanciectasia突变（ATM）基因及其下游合作伙伴和效应器的途径对于DNA损伤反应至关重要。细胞存活，增殖和组织稳态依赖于保存DNA完整性，但额外的细胞内机制有助于这些过程。随着ATM途径中具有有益交叉口的受体介导的信号传导可以具有治疗意义，我们使用HUH-7细胞（肝细胞）的测定询问这种交叉点。将这些细胞进行乙酰氨基酚毒性，这是人们肝损伤和急性肝衰竭的主要原因。在Huh-7-ATM-PROM-TDT细胞中检查ATM途径，含有ATM启动子活性的荧光TD-番茄转基因报告机。滴定剂量的特异性生长因子用作受体介导的信号传导的配体。 JAK / Stat3信令的贡献由jak拮抗剂，ruxolitinib的功能丧失方法定义。在这些测定中，通过选定的生长因子改善乙酰氨基酚毒性后的ATM相关DNA损伤的损伤，包括成纤维细胞生长因子，粒细胞菌落刺激因子和血管内皮生长因子。 Jak / Stat3信号传导是颗粒细胞殖民群刺激因子，但在其他生长因子的情况下涉及额外的途径。 jak / stat3对ruxolitinib的拮抗作用在ATM途径介导的DNA修复中的益处;并鉴定细胞保护的ruxolitinib敏感组分允许这些途径交叉的分离。因此，途径ATM和其他调节剂的这种减去方法将是DNA损伤反应的信息。这些机制将使ATM相关组织和器官受伤的治疗发育。

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