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.

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

“…We found that upregulation of p38β, but not p38α, is a common event in AML cases that contributes to the SET-dependent inactivation of PP2A in AML, pointing to a relevant role of p38β in this aggressive disease. It has been reported that PP2A can regulate p38 signaling pathway, and that PP2A and p38 form complexes in the cytoplasm in basal conditions; in fact, p38 may act as scaffold protein for NMP and PP2A [42][43][44][45] . However, the nature of their connection varies depending on the context.…”

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

“…Yet, the role of PP2a in deactivation of p38 remains cell type- and stimuli-dependent. Indeed, inhibition of PP2A in endothelial cells is associated with increased phosphorylation of p38 in unstimulated cells but does not affect oxidative stress-induced p38 activation [ 56 ]. Interestingly, in endothelial cells, MAP kinase phosphatase-1 (MKP-1) is also a negative regulator of p38 activity and p38-dependant VCAM expression in response to shear stress [ 57 ].…”

“…Endogenous ROS are mainly produced by the mitochondrial respiratory chain and also by enzymatic reactions involving NADPH oxidase (NOX), xanthine oxidase, nitric oxide synthase (NOS), arachidonic acid, and metabolizing enzymes such as the cytochrome P450 enzymes, lipoxygenase, and cyclooxygenase [ 103 ]. Exogenous sources of ROS are generated mainly by ionizing radiation, UV, xenobiotics and pollutants [ 56 ].…”

Research Progress on Signaling Pathway‐Associated Oxidative Stress in Endothelial Cells

“…P38MAPK also functions to control proliferation, differentiation, and migration of endothelial cells. A recent study revealed that as a newly discovered partner of p38 in HUVECs, nucleophosmin (NPM) impairs DNA damage response [15]. …”