Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress‐activated protein kinases/JNKs through its nucleoside diphosphate kinase activity

Abstract

(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.

Extreme heterogeneity of influenza virus infection in single cells

“… Table delineating genes in Figure 9 that are associated with the response to oxidative stress ( Duong et al, 2017 ; Jung et al, 2017 ; Lee and Ryu, 2017 ; Peuchant et al, 2017 ; MacLeod et al, 2016 ; Jiang et al, 2016 ; Gorrini et al, 2013 ; Miura et al, 2013 ; Kim et al, 2010 ; Banning et al, 2005 ; Murray et al, 2003 ; Doyle et al, 1999 ). …”

The relationship of NM23 (NME) metastasis suppressor histidine phosphorylation to its nucleoside diphosphate kinase, histidine protein kinase and motility suppression activities

“…The role of NME enzymatic activities has been less certain. Roles for the NME NDPK activity in the provision of certain nucleotides have been reported to contribute to dynamin function [ 55 ], oxidative stress [ 56 ], and endothelial contractility [ 57 ]. The NDPK activity of NME is not the only enzymatic activity emanating from its histidine 118 autophosphorylation, NME can also serve as a HPK.…”

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“…The role of NME enzymatic activities has been less certain. Roles for the NME NDPK activity in the provision of certain nucleotides have been reported to contribute to dynamin function [55], oxidative stress [56], and endothelial contractility [57]. The NDPK activity of NME is not the only enzymatic activity emanating from its histidine 118 autophosphorylation, NME can also serve as a HPK.…”