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Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin‐mediated signaling to DNA damage response
Author(s) -
Guillonneau Maëva,
Paris François,
Dutoit Soizic,
Estephan Hala,
Bénéteau Elise,
Huot Jacques,
Corre Isabelle
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201500194r
Subject(s) - nucleophosmin , dna damage , protein phosphatase 2 , microbiology and biotechnology , oxidative stress , p38 mitogen activated protein kinases , dephosphorylation , phosphorylation , signal transduction , protein kinase a , biology , chemistry , phosphatase , biochemistry , dna , gene
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 H 2 O 2 , 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. FASEB J. 30, 2899‐2914 (2016). www.fasebj.org