A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress (Retracted article. See vol. 17, pg. 1944, 2010)
A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress (Retracted article. See vol. 17, pg. 1944, 2010)
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DOI：
10.1038/cdd.2008.151
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发表时间：
2009-02-01
影响因子：
12.4
通讯作者：
Shen, H-M
中科院分区：
文献类型：
--
作者：
Huang, Q.;Wu, Y-T;Shen, H-M
在氧化应激下，聚（ADP-核糖）聚合酶-1（PARP-1）被激活，并通过ATP耗竭导致坏死性细胞死亡。另一方面，已知氧化应激刺激自噬，并且自噬可以充当细胞死亡或细胞存活机制。本研究旨在探讨PARP-1在氧化应激介导的自噬和坏死性细胞死亡中的调节作用。在这里，我们首先表明，过氧化氢（H2 O2）诱导Bax-/-巴克-/-小鼠胚胎成纤维细胞的坏死性细胞死亡，通过涉及PARP-1激活和ATP耗竭的机制。接下来，我们提供了自噬在暴露于H2 O2的细胞中被激活的证据。更重要的是，我们确定了一种新的自噬信号机制，将PARP-1与丝氨酸/苏氨酸蛋白激酶LKB 1-AMP激活的蛋白激酶（AMPK）-哺乳动物雷帕霉素靶蛋白（mTOR）通路连接起来，从而刺激自噬。最后，我们证明了自噬在H2 O2诱导的坏死性细胞死亡中起着细胞保护作用，因为通过敲低自噬相关基因ATG 5或ATG 7来抑制自噬极大地增敏了H2 O2诱导的细胞死亡。总之，这些发现证明了PARP-1的一种新功能：通过LKB 1-AMPK-mTOR途径促进自噬，以增强氧化应激下细胞的存活。
Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H2O2) induces necrotic cell death in Bax-/- Bak-/- mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H2O2. More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H2O2-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H2O2-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress.