期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 108, 期 -, 页码 770-784出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2017.04.018
关键词
PARP-1 inhibition; MKP-1; Dusp1; CREB; CREB2; ATF4; P38 MAPK; JNK; Cancer Stem cells; Oxidative stress; ROS
资金
- European Union
- State of Hungary
- European Social Fund [TAMOP 4.2.4. A/2-11-1-2012-0001]
- Janos Bolyai Scholarship of the Hungarian Academy of Science [OTKA K-104220, OTKA NN109841, AOK-KA-34039-10-24, AOK-KA-OTKA-34039]
- [GINOP-2.3.2-15-2016-00049]
- [2.3.3-15-2016-00025]
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.
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