title: Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe.
abstract: Prolonged mitosis due to aberrant chromosome segregation permits cells to enter the G1 phase without cytokinesis and subsequently triggers the p53-dependent cell death program, known as mitotic catastrophe. Cells which fail to go through mitotic catastrophe create aneuploidy, posing a risk of oncogenesis. In the present report, we show that p62-mediated non-canonical activation of Nrf2 leads to the persistent expression of Nqo1, which plays a critical role for p53 stabilization during mitotic catastrophe. With prolonged exposure to nocodazole, a microtubule-depolymerizing agent, p62-deficient HCT116 cells exhibited an accumulation of a polyploid population with a limited appearance of apoptotic cells, which was attributable to the attenuated stabilization of p53. Combinatorial gene manipulation analysis verified that the regulatory cascade with a hierarchy of p62-Keap1-Nrf2-Nqo1 is required for p53 stabilization for mitotic catastrophe. This is consistent with the role of Nqo1 as a gatekeeper for proteasomal degradation of p53. Thus, we demonstrate for the first time the functional connection between the non-canonical Nrf2 pathway and p53-dependent cell death program upon prolonged mitosis.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute, Suwon-Si, Kyonggi-Do, Republic of Korea.
authors.forename: Chi-Bao
authors.initials: CB
authors.lastname: Bui
authors.forename: Jaekyoon
authors.initials: J
authors.lastname: Shin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000782:Aneuploidy; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008938:Mitosis; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D046988:Proteasome Endopeptidase Complex; D015739:Nocodazole