Our recent studies indicate that the oncogenes of DNA viruses differ in their abilities to induce, in the cells they transform, susceptibility to destruction by host celular immune defenses (cytolytic susceptibility). It has also been found that the cytolytic susceptible transformed cell phenotype may be actively regulated by the function of a single viral oncogene. Expression of this oncogene-induced cell phenotype is independent of oncogene transforming activity and of target cell surface expression of histocompatibility antigens and is also apparently unrelated to cell surface expression of oncogene-encoded products. The independent and combined activities of different types of oncogenes that determine susceptibility or resistance of transformed cells to destruction by host mononuclear inflammatory cells will be defined using natural killer cells, activated macrophages and cytotoxic T lymphocytes (effector cells). The mechanisms by which oncogenes regulate susceptibility and resistance to the cytolytic activities of such effector cells will be studied by examining the effects of oncogene expression on (a) transformed cell membrane targets of effector cells, on (b) transformed cell induction of host cytotoxic inflammatory responses and on (c) elaboration by transformed cells of products that effect killer cell migration and function. Transient oncogene expression assays (by protoplast fusion and microinjection) will be used to study effects of oncogene products on cellular cytolytic susceptibility independent of transformation and to develop strategies for cloning transformed cell gene(s) that regulate neoplastic cell cytolytic susceptibility. Studies of in vivo tumor induction by oncogene-transformed cells in hosts with different abilities to mount a cell-mediated immune response will be performed to evaluate the relevance of in vitro observations for tumorigenicity. Attempts will also be made to alter tumorigenicity by introducing into transformed cells oncogenes with known in vitro effects on the cytolytic susceptible transformed cell phenotype. These studies of oncogene functions, as they affect interactions between neoplastic cells and anti-neoplastic host cellular immune defenses should provide new insights into reasons for tumor progression in the immunocompetent host.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043187-03
Application #
3185191
Study Section
Experimental Immunology Study Section (EI)
Project Start
1986-08-01
Project End
1990-07-31
Budget Start
1988-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Cook, J L; Routes, B A; Walker, T A et al. (1999) E1A oncogene induction of cellular susceptibility to killing by cytolytic lymphocytes through target cell sensitization to apoptotic injury. Exp Cell Res 251:414-23
Cook, J L; Routes, B A; Leu, C Y et al. (1999) E1A oncogene-induced cellular sensitization to immune-mediated apoptosis is independent of p53 and resistant to blockade by E1B 19 kDa protein. Exp Cell Res 252:199-210
Cook, J L; Potter, T A; Bellgrau, D et al. (1996) E1A oncogene expression in target cells induces cytolytic susceptibility at a post-recognition stage in the interaction with killer lymphocytes. Oncogene 13:833-42
Cook, J L; Krantz, C K; Routes, B A (1996) Role of p300-family proteins in E1A oncogene induction of cytolytic susceptibility and tumor cell rejection. Proc Natl Acad Sci U S A 93:13985-90
Routes, J M; Cook, J L (1995) E1A gene expression induces susceptibility to killing by NK cells following immortalization but not adenovirus infection of human cells. Virology 210:421-8
Cook, J L; Ikle, D N; Routes, B A (1995) Natural killer cell ontogeny in the athymic rat. Relationship between functional maturation and acquired resistance to E1A oncogene-expressing sarcoma cells. J Immunol 155:5512-8
Routes, J M; Metz, B A; Cook, J L (1993) Endogenous expression of E1A in human cells enhances the effect of adenovirus E3 on class I major histocompatibility complex antigen expression. J Virol 67:3176-81
Routes, J M; Bellgrau, D; McGrory, W J et al. (1991) Anti-adenovirus type 5 cytotoxic T lymphocytes: immunodominant epitopes are encoded by the E1A gene. J Virol 65:1450-7
Walker, T A; Wilson, B A; Lewis Jr, A M et al. (1991) E1A oncogene induction of cytolytic susceptibility eliminates sarcoma cell tumorigenicity. Proc Natl Acad Sci U S A 88:6491-5
Routes, J M; Cook, J L (1990) Resistance of human cells to the adenovirus E3 effect on class I MHC antigen expression. Implications for antiviral immunity. J Immunol 144:2763-70

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