title: PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1.
abstract: p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis.
authors.affiliation: Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Life Science and Ewha Research Center for Systems Biology, Republic of Korea; The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Da Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Electronic address: soohanbae@yuhs.ac.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; D007093:Imidazoles; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C552719:PF-4708671; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse
keywords: Autophagy; Kelch-like ECH-associated protein 1 (Keap1); Nuclear factor erythroid 2-related factor 2 (Nrf2); PF-4708671; p62; p70 ribosomal S6 kinase 1 (S6K1)