Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences

1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico 2 Department of Pathology, National Cancer Institute, Mexico City, Mexico Correspon...

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Published in:Journal of general virology 2005-09, Vol.86 (9), p.2459-2468
Main Authors: De la Cruz-Hernandez, Erick, Garcia-Carranca, Alejandro, Mohar-Betancourt, Alejandro, Duenas-Gonzalez, Alfonso, Contreras-Paredes, Adriana, Perez-Cardenas, Enrique, Herrera-Goepfert, Roberto, Lizano-Soberon, Marcela
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Female
Fundamental and applied biological sciences. Psychology
Genetic Variation
HeLa Cells
Human papillomavirus 18
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Microbiology
Miscellaneous
NIH 3T3 Cells
Oncogene Proteins, Viral - genetics
Oncogene Proteins, Viral - metabolism
Papillomaviridae - classification
Papillomaviridae - genetics
Papillomaviridae - pathogenicity
Papillomavirus Infections - physiopathology
Papillomavirus Infections - virology
RNA Splicing
Uterine Cervical Neoplasms - physiopathology
Uterine Cervical Neoplasms - virology
Virology
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Summary:1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico 2 Department of Pathology, National Cancer Institute, Mexico City, Mexico Correspondence Marcela Lizano-Soberón lizano{at}servidor.unam.mx Persistent infections of the uterine cervix with ‘high-risk’ human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (Asian–Amerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the Asian–Amerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the Asian–Amerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.
ISSN:0022-1317
1465-2099
DOI:10.1099/vir.0.80945-0