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              <p>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 NPM/p38 interaction in basal condition. Oxidative stress, which was generated by exposure to 500 mM 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, 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, 000–000 (2016). www.fasebj.org KEY WORDS: reactive oxygen species • p38 MAPK • endothelial dysfunction • phosphatases • double-strand breaks Endothelial cells are heavily exposed to reactive oxygen species (ROS), generated either from endogenous (oxidative enzymes and mitochondria) or exogenous [inflammatory cytokines, xenobiotics, and ionizing radiation (IR)] sources (1). ROS profoundly affects the functions of endothelial cells (2), notably by inducing many morphologic and functional changes, such as major cytoskeleton reorganization (3) and increased permeability (4), up-regulation of adhesion molecules (5, 6), modulation of angiogenesis (7), genomic instability via DNA damage (8), and cell death (9, 10). Alterations of these endothelial functions link oxidative stress not only to such severe cardiovascular pathologies as atherosclerosis (11, 12) and hypertension (13) but also to diabetes (14) and early and late toxicity to normal tissue induced by IR (15). Understanding the molecular mechanisms that underlie endothelial dysfunction in response to oxidative stress remains an important issue. A major oxidative stress–induced signaling pathway involves members of the p38 MAPK cascade (16). p38 MAPKs are serine/threonine kinases of the stress-activated protein kinase family along with c-Jun N-terminal kinase. The p38 family contains 4 isoforms (a, b, g, and d) that are expressed in function of cell types and are activated in response to a large number of chemical, bi-ologic, and physical stresses (17). p38a is the most widely expressed and studied member of the family and is here referred to as p38 (18). p38 activation leads to subsequent phosphorylation and activation of diverse cytoplasmic and nuclear targets that are involved in a broad range of cellular functions, such as proliferation, differentiation, migration, and survival (17). Notably, activation of p38 in response to oxidative stress in endothelial cells induces a quick and</p>
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