Our recent studies on the mechanism of HSV-2 induced transformation have shown that: (i) neoplastic transformation of normal diploid cells is mediated by the Bg1 II C fragment of HSV-2 DNA (0.416-0.580 map units), (ii) the transformation process involves at least two steps: cellular immortalization mediated by sequences within 0.410-0.525 map units, and the acquisition of neoplastic potential that requires sequences within 0.525-0.580 map units on the HSV-2 genome (presumptive neoplastic sequences), and (iii) the expression of a viral protein designated ICP 10 that is encoded within the presumptive neoplastic sequences correlates with the acquisition of anchorage independent growth and tumorigenic potential by HSV-2 transformed cells. The studies proposed in this application are designed to obtain a better understanding of the role played by the presumptive neoplastic sequences and the proteins that they encode, primarily ICP10, in neoplastic transformation.
The specific aims are: (i) to determine and compare the transforming activities of the subfragments of the presumed neoplastic sequences, in transforming activities of the subfragments of the presumed neoplastic sequences, in various combinations with immortalizing sequences and the sequences homologous to the various combinations with immortalizing sequences and the sequences homologous to the mammalian cell genome, (ii) to determine and compare the transforming activities (at 34 and 39 C) of the tsA8 mutant (in 130K and ICP 10 proteins) before and after marker rescue of the conditionally lethal function (in 130K), (iii) to inhibit ICP 10 synthesis with an oligonucleoside methylphosphonate complementary to the translation initiation region of the ICP 10 mRNA and determine the effect on transformation, (iv) to define and identify DNA sequences homologous to the presumptive neoplastic sequences in the transformed lines and their potential interaction with hamster cell DNA sequences and (v) to identify viral proteins in the transformed cells with particular emphasis on ICP 10, a protein that is encoded by the presumptive neoplastic sequences. These studies should provide a better understanding of the mechanism of HSV-2 induced neoplastic transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039691-03
Application #
3179019
Study Section
Virology Study Section (VR)
Project Start
1985-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zhu, J; Aurelian, L (1997) AP-1 cis-response elements are involved in basal expression and Vmw110 transactivation of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). Virology 231:301-12
Nelson, J W; Zhu, J; Smith, C C et al. (1996) ATP and SH3 binding sites in the protein kinase of the large subunit of herpes simplex virus type 2 of ribonucleotide reductase (ICP10). J Biol Chem 271:17021-7
Smith, C C; Luo, J H; Aurelian, L (1996) The protein kinase activity of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) fused to the extracellular domain of the epidermal growth factor receptor is ligand-inducible. Virology 217:425-34
Hunter, J C; Smith, C C; Bose, D et al. (1995) Intracellular internalization and signaling pathways triggered by the large subunit of HSV-2 ribonucleotide reductase (ICP10). Virology 210:345-60
Smith, C C; Luo, J H; Hunter, J C et al. (1994) The transmembrane domain of the large subunit of HSV-2 ribonucleotide reductase (ICP10) is required for protein kinase activity and transformation-related signaling pathways that result in ras activation. Virology 200:598-612
Smith, C C; Kulka, M; Wymer, J P et al. (1992) Expression of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) is required for virus growth and neoplastic transformation. J Gen Virol 73 ( Pt 6):1417-28
Wymer, J P; Aprhys, C M; Chung, T D et al. (1992) Immediate early and functional AP-1 cis-response elements are involved in the transcriptional regulation of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). Virus Res 23:253-70
Luo, J H; Aurelian, L (1992) The transmembrane helical segment but not the invariant lysine is required for the kinase activity of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). J Biol Chem 267:9645-53
Chung, T D; Luo, J H; Wymer, J P et al. (1991) Leucine repeats in the large subunit of herpes simplex virus type 2 ribonucleotide reductase (RR;ICP10) are involved in RR activity and subunit complex formation. J Gen Virol 72 ( Pt 5):1139-44
Smith, C C; Wymer, J P; Luo, J et al. (1991) Genomic sequences homologous to the protein kinase region of the bifunctional herpes simplex virus type 2 protein ICP10. Virus Genes 5:215-26

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