title: The human DEK proto-oncogene is a senescence inhibitor and an upregulated target of high-risk human papillomavirus E7.
abstract: The human DEK proto-oncogene is a nucleic acid binding protein with suspected roles in human carcinogenesis, autoimmune disease, and viral infection. Intracellular DEK functions, however, are poorly understood. In papillomavirus-positive cervical cancer cells, downregulation of viral E6/E7 oncogene expression results in cellular senescence. We report here the specific repression of DEK message and protein levels in senescing human papillomavirus type 16- (HPV16-) and HPV18-positive cancer cell lines as well as in primary cells undergoing replicative senescence. Cervical cancer cell senescence was partially overcome by DEK overexpression, and DEK overexpression was sufficient for extending the life span of primary keratinocytes, supporting critical roles for this molecule as a senescence regulator. In order to determine whether DEK is a bona fide HPV oncogene target in primary cells, DEK expression was monitored in human keratinocytes transduced with HPV E6 and/or E7. The results identify high-risk HPV E7 as a positive DEK regulator, an activity that is not shared by low-risk HPV E7 protein. Experiments in mouse embryo fibroblasts recapitulated the observed E7-mediated DEK induction and demonstrated that both basal and E7-induced regulation of DEK expression are controlled by the retinoblastoma protein family. Taken together, our results suggest that DEK upregulation may be a common event in human carcinogenesis and may reflect its senescence inhibitory function.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Trisha M
authors.initials: TM
authors.lastname: Wise-Draper
authors.forename: Hillary V
authors.initials: HV
authors.lastname: Allen
authors.forename: Megan N
authors.initials: MN
authors.lastname: Thobe
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Jones
authors.forename: Kristen B
authors.initials: KB
authors.lastname: Habash
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics* / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000503:physiopathology; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014412:Tumor Virus Infections / Q000503:physiopathology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins