Neural precursor cell‐expressed, developmentally down‐regulated 4 (NEDD4) regulates hydrogen peroxide‐induced cell proliferation and death through inhibition of Hippo signaling

E3 ubiquitin ligases are involved in the regulation of oxidative stress-induced cell death. In this study, we investigated the role of neural precursor cell-expressed, developmentally down-regulated protein 4 (NEDD4) in regulation of hydrogen peroxide (H₂O₂)-induced cell proliferation and apoptosis in human bone marrow-derived stem cells (hBMSCs). Cell proliferation was increased in low doses of H₂O₂ (10^-4 to 10^-2 μM), whereas sublethal concentrations of H₂O₂ (>200 μM) induced apoptosis. A chromatin immunoprecipitation assay identified that recruitment of NF-κB onto the promoter region of NEDD4 mediated H₂O₂-induced NEDD4 expression. The increase of NEDD4 expression by H₂O₂ induced translocation of yes-associated protein (YAP) into the nucleus by decreasing the stability of large tumor suppressor kinase (LATS). Thus, the phosphorylation of serine 127 residue of YAP by LATS upstream kinase is decreased and thereby increased the transcriptional activity of YAP. The mRNA expression levels of catalase and manganese superoxide dismutase, which are well-known targets of YAP, were increased by H₂O₂ treatment but down-regulated by NEDD4 silencing using a specific small interfering RNA targeting NEDD4 (siNEDD4). H₂O₂-induced scavenging capacity of reactive oxygen species was also decreased by siNEDD4 in hBMSCs. Finally, hBMSC differentiation into osteoblast was decreased by siNEDD4 but reverted by reintroduction of the S127A mutant construction of YAP. Taken together, these results indicate that NEDD4 regulates H₂O₂-induced alteration of cell status through regulation of the Hippo signaling pathway.-Jeon, S.-A., Kim, D. W., Cho, J.-Y. Neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) regulates hydrogen peroxide-induced cell proliferation and death through inhibition of Hippo signaling.