Herpesvirus saimiri (HVS) induces a rapidly progressing lymphoproliferative disease in primates. The proposed research is directed toward investigating the molecular mechanism of cell growth transformation induced by the HVS STP (saimiri transforming protein). Our work to date has defined that the HVS STP oncogene is not required for viral replication, but it is required for primary lymphoid cell immortalization in culture and lymphoma induction in marmosets. Sequence divergence and transforming activity of the STP gene defines three subgroups (A, B, and C) of HVS that differ with respect to their in vitro and in vivo oncogenic potential: STP of subgroup A (STP-A) is modestly oncogenic, STP of subgroup B (STP-B) is non-oncogenic, and STP of subgroup C (STP-C) is highly oncogenic. Furthermore, while all STP alleles target the TNF receptor associated factor (TRAF) as a common molecule, each allele also targets distinct cellular signaling molecules as additional means to elicit a potent signal transduction cascade. Based on our preliminary results, we hypothesize that a common theme of the STP signal pathway is the induction of TRAF-mediated signal transduction, which leads to the activation of NF-KappaB and AP-1 activity. Additionally, the STP allele of each HVS subgroup induces a complementary pathway by targeting distinct sets of cellular protein that provides additional signaling activation: STAT3 and Src for STP-A and Ras and SGT for STP-C. Ultimately, the cooperation of both the common and complementary STP signal pathways induces a potent activation of virus-infected cells, resulting in transformation of a normal cell to a cancerous cell. Our biochemical and cell biological studies will define in greater detail the mechanisms used by STP-A and STP-C to elicit both common and complementary signal transduction. To correlate the effects of STP on cellular signal transduction with disease induction, we will test whether recombinant HVS containing STP mutants is able to induce the immortalization of primary T lymphocytes in vitro and lymphoma in common marmosets. With well-established experimental conditions, the proposed study will detail the molecular basis of STP-induced cell growth transformation and its contribution to HVS oncogenesis.
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