Artemis is a negative regulator of p53 in response to oxidative stress.
Artemis is a negative regulator of p53 in response to oxidative stress.
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DOI：
10.1038/onc.2009.100
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发表时间：
2009-06-04
期刊：
影响因子：
8
通讯作者：
Legerski, R. J.
中科院分区：
文献类型：
--
作者：
Zhang, X.;Zhu, Y.;Geng, L.;Wang, H.;Legerski, R. J.
Artemis是一种多功能的磷酸化蛋白，参与V(D)J重组，通过非同源末端连接修复双链断裂，以及在DNA损伤后调节细胞周期检查点。在这里，我们描述了Artemis的一个新功能，即在原代细胞和癌细胞系中作为P53的负调节因子来响应氧化应激。我们发现，在典型的培养条件下(21%氧气)，Artemis的耗尽会导致P53的自发磷酸化和稳定化，并导致细胞G1停滞和细胞凋亡。这些作用可被DNA-PKcs共耗尽抑制，但不能被ATM抑制，这表明Artemis是DNA-PKcs介导的P53稳定的抑制物。在3%的氧气中培养细胞或用抗氧化剂处理都破坏了P53的稳定性，这表明氧化应激是负责的细胞刺激。IR或过氧化氢处理不能引起这一信号通路的激活，而线粒体电子传递的抑制剂有效地减少了它的激活。此外，我们还发现参与还原活性氧物种(ROS)的P53可诱导基因在Artemis耗竭后上调。这些发现表明Artemis和DNA-PKcs参与了一种新的信号通路，以调节P53功能，以响应线粒体呼吸产生的氧化应激。
Artemis is a multifunctional phospho-protein with roles in V(D)J recombination, repair of double-strand breaks by nonhomologous end-joining, and regulation of cell cycle checkpoints after DNA damage. Here, we describe a novel function of Artemis as a negative regulator of p53 in response to oxidative stress in both primary cells and cancer cell lines. We show that depletion of Artemis under typical culture conditions (21% oxygen) leads to a spontaneous phosphorylation and stabilization of p53, and resulting cellular G1 arrest and apoptosis. These effects are suppressed by co-depletion of DNA-PKcs, but not ATM, indicating that Artemis is an inhibitor of DNA-PKcs-mediated stabilization of p53. Culturing of cells at 3% oxygen or treatment with an antioxidant abrogated p53 stabilization indicating that oxidative stress is the responsible cellular stimulus. Treatment with IR or hydrogen peroxide did not cause activation of this signaling pathway, while inhibitors of mitochondrial electron transport were effective in reducing its activation. In addition, we show that p53-inducible genes involved in reducing reactive oxygen species (ROS) are upregulated by Artemis depletion. These findings indicate that Artemis and DNA-PKcs participate in a novel, signaling pathway to modulate p53 function in response to oxidative stress produced by mitochondrial respiration.
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影响因子：
5.7
作者：
Chen, L;Morio, T;Mizutani, S
通讯作者：
Mizutani, S
影响因子：
64.5
作者：
SCHEFFNER, M;HUIBREGTSE, JM;HOWLEY, PM
通讯作者：
HOWLEY, PM
影响因子：
5.3
作者：
Geng, Liyi;Zhang, Xiaoshan;Legerski, Randy J.
通讯作者：
Legerski, Randy J.
DOI：
10.1073/pnas.0308757101
发表时间：
2004-02-24
影响因子：
11.1
作者：
Rooney, S;Sekiguchi, J;Alt, FW
通讯作者：
Alt, FW
影响因子：
5.8
作者：
Chang, NS;Doherty, J;Oppermann, U
通讯作者：
Oppermann, U