Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion.
Role of a DNA damage checkpoint pathway in ionizing radiation-induced glioblastoma cell migration and invasion.
复制标题
DNA 损伤检查点通路在电离辐射诱导的胶质母细胞瘤细胞迁移和侵袭中的作用。
DOI：
10.1007/s10571-012-9846-y
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发表时间：
2012
影响因子：
4
通讯作者：
Ruggieri,Rosamaria
中科院分区：
文献类型：
--
作者：
Vanan,Issai;Dong,Zhiwan;Tosti,Elena;Warshaw,Gregg;Symons,Marc;Ruggieri,Rosamaria
电离辐射（IR）诱导DNA损伤反应，包括激活细胞周期检查点，导致细胞周期停滞。此外，IR增强胶质母细胞瘤细胞以及其他肿瘤细胞类型的细胞侵袭力。使用RNA干扰，我们发现，蛋白激酶MRK，以前牵连的DNA损伤反应IR，也抑制IR诱导的细胞迁移和胶质母细胞瘤细胞的侵袭。我们发现IR激活MRK需要检查点蛋白Nbs 1，并且Nbs 1也是IR刺激的迁移所需的。此外，我们发现MRK作用于Chk 2的上游，并且Chk 2也是IR刺激的迁移和侵袭所需的。因此，我们已经确定Nbs 1，MRK和Chk 2作为一种新的信号通路，介导IR刺激的细胞迁移和入侵的元素。有趣的是，我们发现，抑制细胞周期的进展，无论是与CDK 1/2抑制剂CGP 74514 A或下调的CDC 25 A蛋白磷酸酶，恢复IR诱导的迁移和侵袭细胞耗尽的MRK或Chk 2。这些数据表明，至少在IR的背景下，细胞周期进程对胶质母细胞瘤细胞的侵袭特性施加负控制，并且检查点蛋白通过控制细胞周期停滞来介导IR诱导的侵袭行为。
Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IR-induced invasive behavior by controlling cell cycle arrest.