title: DEK over-expression promotes mitotic defects and micronucleus formation.
abstract: The DEK gene encodes a nuclear protein that binds chromatin and is involved in various fundamental nuclear processes including transcription, RNA splicing, DNA replication and DNA repair. Several cancer types characteristically over-express DEK at the earliest stages of transformation. In order to explore relevant mechanisms whereby DEK supports oncogenicity, we utilized cancer databases to identify gene transcripts whose expression patterns are tightly correlated with that of DEK. We identified an enrichment of genes involved in mitosis and thus investigated the regulation and possible function of DEK in cell division. Immunofluorescence analyses revealed that DEK dissociates from DNA in early prophase and re-associates with DNA during telophase in human keratinocytes. Mitotic cell populations displayed a sharp reduction in DEK protein levels compared to the corresponding interphase population, suggesting DEK may be degraded or otherwise removed from the cell prior to mitosis. Interestingly, DEK overexpression stimulated its own aberrant association with chromatin throughout mitosis. Furthermore, DEK co-localized with anaphase bridges, chromosome fragments, and micronuclei, suggesting a specific association with mitotically defective chromosomes. We found that DEK over-expression in both non-transformed and transformed cells is sufficient to stimulate micronucleus formation. These data support a model wherein normal chromosomal clearance of DEK is required for maintenance of high fidelity cell division and chromosomal integrity. Therefore, the overexpression of DEK and its incomplete removal from mitotic chromosomes promotes genomic instability through the generation of genetically abnormal daughter cells. Consequently, DEK over-expression may be involved in the initial steps of developing oncogenic mutations in cells leading to cancer initiation.
authors.affiliation: a Cancer and Blood Diseases Institute; Cincinnati Children's Hospital Medical Center and University of Cincinnati ; Cincinnati , OH USA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Matrka
authors.affiliation: a Cancer and Blood Diseases Institute; Cincinnati Children's Hospital Medical Center and University of Cincinnati ; Cincinnati , OH USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hennigan
authors.affiliation: b Department of Biological Sciences ; Xi'an Jiaotong-Liverpool University , Suzhou , Jiangsu Province , China.|c Institute of Biochemistry and Molecular Biology; Medical School; RWTH Aachen University ; Aachen , Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Kappes
authors.affiliation: d Division of Rheumatology; Cincinnati Children's Hospital Medical Center ; Cincinnati , OH USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: DeLay
authors.affiliation: e McArdle Laboratory for Cancer Research; University of Wisconsin-Madison School of Medicine and Public Health ; Madison , WI USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: f Biomedical Informatics; Cincinnati Children's Hospital Medical Center ; Cincinnati , OH USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: a Cancer and Blood Diseases Institute; Cincinnati Children's Hospital Medical Center and University of Cincinnati ; Cincinnati , OH USA.
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D000705:Anaphase / Q000235:genetics; D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007399:Interphase / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011418:Prophase / Q000235:genetics; D013692:Telophase / Q000235:genetics
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins
keywords: DEK; aneuploidy; cancer; chromosome instability; micronuclei; mitosis; mitotic defects