title: Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response.
abstract: 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.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and Le Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval et le Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.
authors.forename: Maëva
authors.initials: M
authors.lastname: Guillonneau
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and.
authors.forename: François
authors.initials: F
authors.lastname: Paris
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and.
authors.forename: Soizic
authors.initials: S
authors.lastname: Dutoit
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and.
authors.forename: Hala
authors.initials: H
authors.lastname: Estephan
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and.
authors.forename: Elise
authors.initials: E
authors.lastname: Bénéteau
authors.affiliation: Le Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval et le Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Huot
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, Nantes, France; INSERM, Unité Mixte de Recherche 892, Nantes, France; Université de Nantes, Nantes, France; and Le Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval et le Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada isabelle.corre@inserm.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Corre
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D004249:DNA Damage; D042783:Endothelial Cells / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2
keywords: double-strand breaks; endothelial dysfunction; p38 MAPK; phosphatases; reactive oxygen species