title: Deficiency in the nuclear-related factor erythroid 2 transcription factor (Nrf1) leads to genetic instability.
abstract: Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) regulates cellular stress response genes, and has also been suggested to play a role in other cellular processes. We previously demonstrated that hepatocyte-specific deletion of Nrf1 in mice resulted in spontaneous apoptosis, inflammation, and development of liver tumors. Here, we showed that both fibroblasts derived from Nrf1 null mouse embryos and fibroblasts expressing a conditional Nrf1 allele showed increased micronuclei and formation of abnormal nuclei. Lentiviral shRNA-mediated knockdown of Nrf1 in SAOS-2 cells also resulted in increased micronuclei, abnormal mitosis and multi-nucleated cells. Metaphase analyses showed increased aneuploidy in Nrf1(-/-) embryonic fibroblasts. Nuclear defects in Nrf1-deficient cells were associated with decreased expression of various genes encoding kinetochore and mitotic checkpoint proteins. Our findings suggest that Nrf1 may play a role in maintaining genomic integrity, and that Nrf1 dysregulation may induce tumorigenesis.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California at Irvine, USA.
authors.forename: Diane H
authors.initials: DH
authors.lastname: Oh
authors.forename: Diamanda
authors.initials: D
authors.lastname: Rigas
authors.forename: Ara
authors.initials: A
authors.lastname: Cho
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D042822:Genomic Instability; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051265:NF-E2-Related Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050984:NF-E2 Transcription Factor, p45 Subunit; D051265:NF-E2-Related Factor 1; C088357:NFE2L1 protein, human; C494693:Nfe2 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering