We have mapped by S1 and ExoVII digestion and by primer extension viral transcripts in nonvirus producing domestic rabbit papillomas and carcinomas and in virus producing domestic rabbit papillomas and determined their coding capacity. The major transcripts can code for E7 and a truncated E6 protein, and minor ones were identified which can code for E2 and a full sized E6 protein. All early RNA is transcribed from promotors with TATA boxes. Late transcripts of 2.6 and 4.8 kb unique to virus producing tumors code for an L1 and an L2 or possibly an L2-L1 fusion protein. Both share the same leader exon and a capsite located in the untranslated region which is not preceded by a TATA box. This indicates that a switch from early to late transcription involves recognition of a new promotor and suppression of transcription termination at the early polyadenylation site. Expression of early proteins in COS-7 cells has permitted us to identify the E6 protein and preliminary data have also been obtained for E2. DNA analysis of HPV-16 in cervical cancer has shown that in a majority, the HPV-16 DNA is integrated. Some also contain plasmid DNA. Transcript mapping indicated that the major transcripts code for E7 and E6 and it suggests that only integrated DNA is functional and integration, at least of some DNA, may be required for cancer progression. The E7 protein of HPV-16 has been identified as a cytoplasmic phosphoprotein with a short half life. Cottontail rabbit papillomavirus provides the only animal model system and our long term objective is to understand the molecular biology of the virus and particularly how the virus contributes to the development of malignant tumors. In the present application, we propose to: 1) Identify and biochemically characterize ealy viral proteins with respect to subcellular distribution, modification, association with cellular proteins and possible enzymatic activity; 2) Determine their biological function through a genetic analysis in animals and epithelial cell culture; 3) Initiate experiments related to immunologic phenomena.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA018151-15
Application #
3481803
Study Section
Experimental Virology Study Section (EVR)
Project Start
1976-06-30
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
15
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lyratzopoulos, Georgios; Liu, Michael Pang-Hsiang; Abel, Gary A et al. (2015) The Association between Fatalistic Beliefs and Late Stage at Diagnosis of Lung and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 24:720-6
Selvakumar, R; Schmitt, A; Iftner, T et al. (1997) Regression of papillomas induced by cottontail rabbit papillomavirus is associated with infiltration of CD8+ cells and persistence of viral DNA after regression. J Virol 71:5540-8
Harry, J B; Wettstein, F O (1996) Transforming properties of the cottontail rabbit papillomavirus oncoproteins Le6 and SE6 and of the E8 protein. J Virol 70:3355-62
Zeltner, R; Borenstein, L A; Wettstein, F O et al. (1994) Changes in RNA expression pattern during the malignant progression of cottontail rabbit papillomavirus-induced tumors in rabbits. J Virol 68:3620-30
Schmitt, A; Harry, J B; Rapp, B et al. (1994) Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1. J Virol 68:7051-9
Meyers, C; Harry, J; Lin, Y L et al. (1992) Identification of three transforming proteins encoded by cottontail rabbit papillomavirus. J Virol 66:1655-64
Meyers, C; Wettstein, F O (1991) The late region differentially regulates the in vitro transformation by cottontail rabbit papillomavirus DNA in different cell types. Virology 181:637-46
Iftner, T; Sagner, G; Pfister, H et al. (1990) The E7 protein of human papillomavirus 8 is a nonphosphorylated protein of 17 kDa and can be generated by two different mechanisms. Virology 179:428-36
Nasseri, M; Meyers, C; Wettstein, F O (1989) Genetic analysis of CRPV pathogenesis: the L1 open reading frame is dispensable for cellular transformation but is required for papilloma formation. Virology 170:321-5
Barbosa, M S; Wettstein, F O (1988) The two proteins encoded by the cottontail rabbit papillomavirus E6 open reading frame differ with respect to localization and phosphorylation. J Virol 62:1088-92

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