Neuroepithelial carcinomas in mice transgenic with human papillomavirus type 16 E6/E7 ORFs.
The effect of the human papillomavirus (HPV) oncogenes E6 and E7 was examined in transgenic mice with a construct containing the human beta-actin promoter regulating HPV16 E6 and E7 open reading frames. In the sole line of mice that transmitted the transgene, neuroepithelial tumors appeared at 2.5 months of life, and by 10 months, 87 of 122 (71%) of the animals were dead from brain tumors. The most frequent type of tumor (74%) was an anaplastic neuroepithelial tumor associated with the ependyma of the third and fourth ventricles, which locally invaded adjacent brain tissue and spread for considerable distances along the ventricular surface. The other two types of tumor were well-differentiated choroid plexus carcinomas (26%) and rare pituitary carcinomas (8.7%). HPV16 E6 RNA and E7 oncoprotein expression were demonstrated in tumor tissue and primary cell lines derived from the tumors. Examination of two tumor suppressor gene products, the retinoblastoma protein and p53, known to bind to HPV16 E7 and E6 oncoproteins, respectively, showed both were expressed in the primary tumor cell lines. These data support a causative role for the HPV oncoproteins in epithelial carcinogenesis.
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
J M
JM
Arbeit
K
K
Münger
P M
PM
Howley
D
D
Hanahan
D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics*; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D012016:Reference Values; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16