title: E6 and E7 oncoproteins induce distinct patterns of chromosomal aneuploidy in skin tumors from transgenic mice.
abstract: Inactivation of the tumor suppressor genes p53 and Rb are two of the most common genetic alterations in cancer cells. We use a mouse model to dissect the consequences of compromising the function of either of these genes on the maintenance of genomic stability. Thirteen cell lines established from skin tumors of mice expressing either the E6 or E7 oncoprotein of the human papillomavirus (HPV) type 16 under control of the keratin 14 promoter were analyzed by comparative genomic hybridization, spectral karyotyping and fluorescence in situ hybridization, reverse transcription-PCR, and mutation analysis. Deducing from the wealth of molecular cytogenetic data available from human cancers, we hypothesized that the more benign tumors in mice expressing E7 would be distinct from the more aggressive lesions in E6 transgenic mice. Tumorigenesis in E6-expressing mice required specifically the selection and maintenance of cells with extra copies of chromosome 6. Aneuploidy of chromosome 6 was independent of activating mutations in H-ras on chromosome 7. Expression of either E6 or E7 resulted in centrosome aberrations, indicating that each viral oncoprotein interferes independently with the centrosome cycle. Although centrosome aberrations are consistent with development of aneuploidy, no direct correlation was evident between the degree of aneuploidy and the percentage of cells with aberrant centrosomes. Our results show that although aneuploidy and centrosome aberrations are present in tumor cells from mice expressing either E6 or E7, tumorigenesis via E6 requires copy number increases of mouse chromosome 6, which is partially orthologous to human chromosome 3q, a region gained in HPV-associated carcinomas.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, Maryland, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Schaeffer
authors.forename: Marie
authors.initials: M
authors.lastname: Nguyen
authors.forename: Amy
authors.initials: A
authors.lastname: Liem
authors.forename: Denis
authors.initials: D
authors.lastname: Lee
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Difilippantonio
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000782:Aneuploidy; D000818:Animals; D002273:Carcinogens; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics*; D017931:DNA Primers; D016161:Genes, Retinoblastoma / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D007621:Karyotyping; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012097:Repressor Proteins; D012878:Skin Neoplasms / Q000235:genetics* / Q000821:virology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D002273:Carcinogens; D017931:DNA Primers; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate