title: Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration.
abstract: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wild-type and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration.
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana;
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Department of Pathology, Anhui University of Traditional Chinese Medicine, Hefei, China; and.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana;
authors.forename: Joonyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana;
authors.forename: Shashank Manohar
authors.initials: SM
authors.lastname: Nambiar
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana;
authors.forename: Veronica
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana;
authors.forename: Qi
authors.initials: Q
authors.lastname: Bao
authors.affiliation: Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California.
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; gdai@iupui.edu.
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C508184:CCNA2 protein, mouse; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D056751:Cyclin A2; D056744:Cyclin B1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse; D016203:CDC2 Protein Kinase
keywords: hepatocyte mitosis; hepatocyte proliferation; nuclear factor erythroid 2-related factor 2