Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response.
Oxidative stress is a leading cause of endothelial dysfunction. The p38 MAPK pathway plays a determinant role in allowing cells to cope with oxidative stress and is tightly regulated by a balanced interaction between p38 protein and its interacting partners. By using a proteomic approach, we identified nucleophosmin (NPM) as a new partner of p38 in HUVECs. Coimmunoprecipitation and microscopic analyses confirmed the existence of a cytosolic nucleophosmin (NPM)/p38 interaction in basal condition. Oxidative stress, which was generated by exposure to 500 µM H2O2, induces a rapid dephosphorylation of NPM at T199 that depends on phosphatase PP2A, another partner of the NPM/p38 complex. Blocking PP2A activity leads to accumulation of NPM-pT199 and to an increased association of NPM with p38. Concomitantly to its dephosphorylation, oxidative stress promotes translocation of NPM to the nucleus to affect the DNA damage response. Dephosphorylated NPM impairs the signaling of oxidative stress-induced DNA damage via inhibition of the phosphorylation of ataxia-telangiectasia mutated and DNA-dependent protein kinase catalytic subunit. Overall, these results suggest that the p38/NPM/PP2A complex acts as a dynamic sensor, allowing endothelial cells to react rapidly to acute oxidative stress.-Guillonneau, M., Paris, F., Dutoit, S., Estephan, H., Bénéteau, E., Huot, J., Corre, I. Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response.
['Guillonneau|Maëva|M|', 'Paris|François|F|', 'Dutoit|Soizic|S|', 'Estephan|Hala|H|', 'Bénéteau|Elise|E|', 'Huot|Jacques|J|', 'Corre|Isabelle|I|']
D021581:Active Transport, Cell Nucleus D004249:DNA Damage D042783:Endothelial Cells D015971:Gene Expression Regulation, Enzymologic D006801:Humans D009687:Nuclear Proteins D000090243:Nucleophosmin D018384:Oxidative Stress D010766:Phosphorylation D054648:Protein Phosphatase 2 D015398:Signal Transduction D048051:p38 Mitogen-Activated Protein Kinases
endothelial dysfunction p38 MAPK phosphatases double-strand breaks reactive oxygen species