title: Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.
abstract: NME1(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.NME1-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 ofNME1reduced 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 H2O2and 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.NME1-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.
authors.affiliation: Collège Santé Université de Bordeaux, Bordeaux, France.|INSERM 1035, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Peuchant
authors.affiliation: Collège Santé Université de Bordeaux, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Bats
authors.affiliation: Collège Santé Université de Bordeaux, Bordeaux, France.|INSERM 1035, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Moranvillier
authors.affiliation: Université Paris Sud, Commissariat à l'Énergie Atomique et aux Énergies, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 9198, Orsay, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lepoivre
authors.affiliation: Hospices Civils de Lyon, Pierre Bénite, France.|Université de Lyon, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, INSERM, Unité Mixte de Recherche S938, Saint-Antoine Research Center, Paris, France.|Laboratoire d'Anatomie Pathologique, Hôpital Saint-Antoine, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, INSERM, Unité Mixte de Recherche S938, Saint-Antoine Research Center, Paris, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Lacombe
authors.affiliation: Collège Santé Université de Bordeaux, Bordeaux, France.|INSERM 1035, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, INSERM, Unité Mixte de Recherche S938, Saint-Antoine Research Center, Paris, France; mathieu.boissan@inserm.fr.|Service de Biochimie et Hormonologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boissan
authors.affiliation: Collège Santé Université de Bordeaux, Bordeaux, France; sandrine.dabernat@u-bordeaux.fr.|INSERM 1035, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dabernat
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; C517939:Nme1 protein, mouse; D010269:Paraquat
keywords: MAPK; NDPK; hepatocyte; keratinocyte