title: p62 prevents carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell death by activating Nrf2.
abstract: Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) is a mitochondrial depolarizing agent that induces reactive oxygen species (ROS)-mediated cell death. The Nrf2-Keap1 pathway is crucial for the elimination of ROS in stressed cells. However, the molecular mechanism underlying the regulation of the Nrf2-Keap1 pathway in CCCP-induced cell death is unknown. In this study, we demonstrated that CCCP promotes Keap1 degradation, and thereby activates Nrf2. This CCCP-mediated Keap1 degradation is partly dependent on autophagy. Moreover, CCCP-induced Keap1 degradation is mainly reliant on p62, which functions as an adaptor protein during selective autophagy. Lack of p62 blocked CCCP-induced Keap1 degradation and inhibited Nrf2 activation, and thereby increased the accumulation of ROS. Ablation of p62 increased the susceptibility of cells to oxidative stress. These results indicate that p62 plays an important role in protecting cells against oxidative stress through Keap1 degradation-mediated Nrf2 activation.
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 127-750, South Korea; The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, South Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea. Electronic address: soohanbae@yuhs.ac.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone
keywords: Autophagy; CCCP; Keap1; Nrf2; p62