PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway
PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway
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DOI：
10.1016/j.freeradbiomed.2017.04.018
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发表时间：
2017-07-01
影响因子：
7.4
通讯作者：
Racz, Boglarka
中科院分区：
文献类型：
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作者：
Hocsak, Eniko;Szabo, Viktor;Racz, Boglarka
氧化应激诱导DNA断裂和PARP-1激活，从而通过尚不清楚的途径启动线粒体活性氧(ROS)的产生和细胞死亡。在这里，我们展示了PARP-1通过激活转录因子-4(ATF4)的PAR化作用影响这些过程的机制，ATF4负责MAP-1的表达，从而调节MAP激酶。PARP抑制剂或沉默PARP可通过ATF4依赖的方式诱导MKP-1的表达，并使JNK和p38 MAP激酶失活。此外，它还诱导ATF4的表达并与cAMP反应元件(CRE)结合，导致MKP1的表达和MAP激酶的失活。相反，在体外，PARP-1激活诱导ATF4的PAR化，并减少其与Cre序列的结合。芯片定量聚合酶链式反应分析表明，PARP抑制剂增加了MKP-1起始点ATF4的占有率。在氧化应激中，PARP抑制可减少ROS诱导的细胞死亡，抑制线粒体ROS的产生，并通过ATF4和MKP-1依赖的方式保护线粒体膜电位。在WRL-68、A-549和T24/83人细胞系中获得了基本相同的结果，表明上述机制具有普遍性。在这里，我们首次描述了PARP-1-ATF4-MKP-1-JNK/p38 MAPK逆行通路，该通路负责在氧化应激中调节线粒体完整性、ROS产生和细胞死亡，并可能代表PARP在癌症治疗中的一种新机制，因为癌症干细胞的发展是JNK依赖的。
Oxidative stress induces DNA breaks and PARP-1 activation which initiates mitochondrial reactive oxygen species (ROS) production and cell death through pathways not yet identified. Here, we show the mechanism by which PARP-1 influences these processes via PARylation of activating transcription factor-4 (ATF4) responsible for MAP kinase phosphatase-1 (MKP-1) expression and thereby regulates MAP kinases. PARP inhibitor, or silencing, of PARP induced MKP-1 expression by ATF4-dependent way, and inactivated JNK and p38 MAP kinases. Additionally, it induced ATF4 expression and binding to cAMP-response element (CRE) leading to MKP1 expression and the inactivation of MAP kinases. In contrast, PARP-1 activation induced the PARylation of ATF4 and reduced its binding to CRE sequence in vitro. CHIP-qPCR analysis showed that PARP inhibitor increased the ATF4 occupancy at the initiation site of MKP-1. In oxidative stress, PARP inhibition reduced ROS-induced cell death, suppressed mitochondrial ROS production and protected mitochondrial membrane potential on an ATF4 and MKP-1 dependent way. Basically identical results were obtained in WRL-68, A-549 and T24/83 human cell lines indicating that the aforementioned mechanism can be universal. Here, we provide the first description of PARP-1-ATF4-MKP-1-JNK/p38 MAPK retrograde pathway, which is responsible for the regulation of mitochondrial integrity, ROS production and cell death in oxidative stress, and may represent a new mechanism of PARP in cancer therapy since cancer stem cells development is JNK-dependent.