The small DNA tumor virus SV40 has served as a long standing, valued tool for investigating mechanisms involved in transformation of cells in culture and tumorigenesis in animal systems. The major viral oncoprotein, the large T antigen (T) is sufficient to activate growth promoting genes, inactivate tumor suppressor genes, modulate oncoprotein-activated cell death pathways, and confer the individual growth behavior changes that collectively constitute the transformed cell phenotype. The overall goal of this research project is to identify the T-antigen activities involved in these processes and determine how they interact to promote transformation and tumorigenesis.
Four specific aims address this initiative. The first investigates activities of T antigen that are required to escape natural senescence and to maintain an immortalized state. We show that excision of T-antigen coding sequences from transformed cells results in cessation of cell growth. We will determine whether individual segments of T antigen that cooperate to immortalize primary cells are needed for immortalization maintenance and the fate of cells from which full-length or segments of T antigen are excised. The second defines the ras-effector pathways and activities involved in T-antigen mediated escape from ras-oncogene induced senescence. Expression of a ras oncogene, although initially mitogenic, induces senescence when prolonged. N- and C-terminal T antigen segments individually bypass this process. We show that full-length T antigen cooperates with either of two ras-effector pathways and that the T-antigen segments require multiple pathways in order to transform primary cells in cooperation with ras. We propose to determine how T antigen and the individual segments interact with individual ras-signal-transduction pathways and how the ras oncogene is involved in the immortalization process.
The third aim further defines T-antigen activities involved in modulating apoptosis induced by the oncogene expression alone or in combination with genotoxic damage and the role of binding the anti-apoptotic cellular protein p193. The results obtained are expected to advance understanding of this complex oncogene and how its interactions with key cellular proteins impact on transformation and oncogenesis.
| Tatum, Angela M; Mylin, Lawrence M; Bender, Susan J et al. (2008) CD8+ T cells targeting a single immunodominant epitope are sufficient for elimination of established SV40 T antigen-induced brain tumors. J Immunol 181:4406-17 |
