title: Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver.
abstract: Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.
authors.affiliation: a Department of Pharmacology; Anhui Medical University; Hefei, China.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zou
authors.forename: Shashank Manohar
authors.initials: SM
authors.lastname: Nambiar
authors.forename: Joonyong
authors.initials: J
authors.lastname: Lee
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse
keywords: Keap1; Nrf2; hepatocyte proliferation; the cell cycle; the redox cycle