Peuchant Evelyne, Bats Marie-Lise, Moranvillier Isabelle, Lepoivre Michel, Guitton Jérôme, Wendum Dominique, Lacombe Marie-Lise, Moreau-Gaudry François, Boissan Mathieu, Dabernat Sandrine
Collège Santé Université de Bordeaux, Bordeaux, France.
INSERM 1035, Bordeaux, France.
FASEB J. 2017 Apr;31(4):1531-1546. doi: 10.1096/fj.201600705R. Epub 2017 Jan 11.
(nonmetastatic expressed 1) gene, which encodes nucleoside diphosphate kinase (NDPK) A [also known as nonmetastatic clone 23 (NM23)-H1 in humans and NM23-M1 in mice], is a suppressor of metastasis, but several lines of evidence-mostly from plants-also implicate it in the regulation of the oxidative stress response. Here, our aim was to investigate the physiologic relevance of NDPK A with respect to the oxidative stress response in mammals and to study its molecular basis. -knockout mice died sooner, suffered greater hepatocyte injury, and had lower superoxide dismutase activity than did wild-type (WT) mice in response to paraquat-induced acute oxidative stress. Deletion of reduced total NDPK activity and exacerbated activation of the stress-related MAPK, JNK, in the liver in response to paraquat. In a mouse transformed hepatocyte cell line and in primary cultures of normal human keratinocytes, MAPK activation in response to HO and UVB, respectively, was dampened by expression of NM23-M1/NM23-H1, dependent on its NDPK catalytic activity. Furthermore, excess or depletion of NM23-M1/NM23-H1 NDPK activity did not affect the intracellular bulk concentration of nucleoside di- and triphosphates. -deficient mouse embryo fibroblasts grew poorly in culture, were more sensitive to stress than WT fibroblasts, and did not immortalize, which suggested that they senesce earlier than do WT fibroblasts. Collectively, these results indicate that the NDPK activity of NM23-M1/NM23-H1 protects cells from acute oxidative stress by inhibiting activation of JNK in mammal models.-Peuchant, E., Bats, M.-L., Moranvillier, I., Lepoivre, M., Guitton, J., Wendum, D., Lacombe, M.-L., Moreau-Gaudry, F., Boissan, M., Dabernat, S. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.
（非转移性表达1）基因编码核苷二磷酸激酶（NDPK）A [在人类中也称为非转移性克隆23（NM23）-H1，在小鼠中称为NM23-M1]，是一种转移抑制因子，但一些证据线索——大多来自植物——也表明它参与氧化应激反应的调节。在这里，我们的目的是研究NDPK A在哺乳动物氧化应激反应方面的生理相关性，并研究其分子基础。与野生型（WT）小鼠相比，NDPK A基因敲除小鼠在百草枯诱导的急性氧化应激反应中死亡更早，肝细胞损伤更严重，超氧化物歧化酶活性更低。NDPK A基因的缺失降低了总NDPK活性，并加剧了肝脏中应激相关的丝裂原活化蛋白激酶（MAPK）即JNK在百草枯作用下的激活。在小鼠转化肝细胞系和正常人角质形成细胞原代培养物中，分别对过氧化氢（HO）和紫外线B（UVB）的反应中，MAPK的激活因NM23-M1/NM23-H1的表达而受到抑制，这依赖于其NDPK催化活性。此外，NM23-M1/NM23-H1 NDPK活性的过量或缺失并不影响细胞内核苷二磷酸和三磷酸的总体浓度。NDPK A基因缺陷的小鼠胚胎成纤维细胞在培养中生长不良，比WT成纤维细胞对压力更敏感，并且不会永生化，这表明它们比WT成纤维细胞更早衰老。总的来说，这些结果表明，在哺乳动物模型中，NM23-M1/NM23-H1的NDPK活性通过抑制JNK的激活来保护细胞免受急性氧化应激。——佩尚特，E.，巴茨，M.-L.，莫兰维利耶，I.，勒普瓦雷，M.，吉顿，J.，温杜姆，D.，拉孔布，M.-L.，莫罗-高德里，F.，布瓦桑，M.，达贝纳特，S. 转移抑制因子NM23通过其核苷二磷酸激酶活性防止应激激活蛋白激酶/JNKs的激活来限制哺乳动物的氧化应激。
