E6 and E7 expression from the HPV 18 LCR: development of genital hyperplasia and neoplasia in transgenic mice.
Human papillomavirus type 18 infection is highly associated with malignant tumors of the genital tract. To investigate the tissue specificity of the HPV long control region (LCR) and the transforming ability of the E6-E7 oncoproteins, an HPV-18 transgene containing the viral LCR and E6 and E7 genes was introduced into mice. Three founder males exhibited enlarged seminal vesicles and preputial glands by 50 weeks of age. A line of transgenic mice was established by in vitro fertilization, and subsequent generations of transgenic males and females were monitored for lesions. Approximately 80% of hemizygous transgenic males exhibited enlarged seminal vesicles and preputial glands as early as 12 weeks of age. Histological examination indicated that this enlargement was due to distension by fluid, along with polyploid hyperplasia of the lining secretory epithelium. E6 and E7 transcripts were limited to affected organs and kidney. Approximately 41% of transgenic females developed cervical neoplasms between 1-2 years of age. Histologically, tumors were mesenchymal rather than epithelial in origin. E6 and E7 transcripts were restricted to cervical tumor tissue and kidney. These findings suggest that the HPV-18 LCR has an element(s) which directs expression specifically to the urogenital tract in transgenic mice.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235.
S A
SA
Comerford
S D
SD
Maika
L A
LA
Laimins
A
A
Messing
H P
HP
Elsässer
R E
RE
Hammer
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins; D005260:Female; D005837:Genitalia, Male / Q000473:pathology / Q000821:virology*; D006965:Hyperplasia / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000821:virology*
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral