The long-term objective of this proposal is to understand the mechanisms of oncogenesis by acutely oncogenic retroviruses. Analysis of this class of oncogenic agents has made significant contributions to our knowledge of the molecular mechanisms that underlie cancer. This proposal focuses on one particular avian retrovirus, reticuloendotheliosis virus strain T, Rev-T. Rev-T is an extremely lethal carcinogenic agent, inducing a rapid and fatal lymphoma in young galliform birds with a latency period of less than two weeks. Rev-T encodes the v-rel oncogene that is solely responsible for the oncogenic properties of Rev-T. The v-rel protein is a member of a ubiquitous transcription factor family that includes both subunits of the mammalian transcription factor Nuclear Factor-Kappa B, NF-kB. The identification of v-rel as a member of this transcription factor family provides a framework for understanding oncogenesis by Rev-T in detailed molecular terms. The v-rel protein is able to inhibit the ability of NF-kB to activate expression from cellular promoters that are responsive to NF-kB. This result has lead to the hypothesis that oncogenesis by Rev-T is the result of a dominant-negative interaction of the v-rel protein and the avian NF-kB proteins. Alternatively, oncogenesis by v-rel might be the result of a regulatory action of v-rel on a unique set of genes independent of the NF-kB proteins. The nature and oncogenic consequences of interactions between the v-rel and NF-kB proteins will be addressed by examining the effects of overexpression of the NF-kB proteins on the oncogenic phenotypes of v-rel transformed lymphoid cells. The cellular homolog, c-rel, of the v-rel oncogene is not oncogenic when expressed in a retrovirus. The structural alterations and biochemical differences between v-rel and c-rel that are sufficient for oncogenic activation of c-rel will be determined. These experiments will address the mechanisms whereby a normal cellular transcription factor can be activated for oncogenesis. The oncogenic property of v-rel suggests that structural alterations to other members of the NF-kB family might also be sufficient for oncogenic activation. The highly mutagenic nature of retrovirus replication will be utilized to obtain mutant NF-kB proteins selected for tumorigenesis in vivo. Analysis of these mutant NF-kB proteins will contribute towards the understanding of the role of the NF-kB/c-rel transcription factor family in oncogenesis.
