Oncology and Cell Biology Center, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
Cell Mol Neurobiol. 2012 Oct;32(7):1199-208. doi: 10.1007/s10571-012-9846-y. Epub 2012 May 3.
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.
电离辐射（IR）会引发 DNA 损伤反应，包括细胞周期检查点的激活，导致细胞周期停滞。此外，IR 还会增强包括神经胶质瘤细胞在内的多种肿瘤细胞类型的侵袭能力。通过 RNA 干扰，我们发现先前涉及 IR 诱导的 DNA 损伤反应的蛋白激酶 MRK，也抑制了神经胶质瘤细胞的 IR 诱导的迁移和侵袭。我们表明，IR 对 MRK 的激活需要检查点蛋白 Nbs1，并且 Nbs1 也是 IR 刺激迁移所必需的。此外，我们还表明，MRK 作用于 Chk2 的上游，并且 Chk2 也是 IR 刺激迁移和侵袭所必需的。因此，我们已经确定 Nbs1、MRK 和 Chk2 是介导 IR 刺激细胞迁移和侵袭的新信号通路的组成部分。有趣的是，我们发现，无论是用 CDK1/2 抑制剂 CGP74514A 抑制细胞周期进程，还是下调 CDC25A 蛋白磷酸酶，都可以恢复 MRK 或 Chk2 耗竭细胞中的 IR 诱导的迁移和侵袭。这些数据表明，细胞周期进程至少在 IR 的背景下，对神经胶质瘤细胞的侵袭特性施加了负向控制，而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。
