The Rel/NF-kB family of transcription factors controls a number of genes involved in key cellular processes, such as proliferation, immune and inflammatory responses, and apoptosis. Expression of mutant Rel transcription factors has also been associated with several animal and human cancers. This application explores the mechanism by which an avian retrovirus malignantly transforms and immortalizes avian lymphoid cells, as a model for the molecular basis of certain human lymphoid cancers that are caused by mutant Rel transcription factors. Specific functions of v-Rel that are important for its ability to transform cells will be investigated. These include the ability of mutant Envelope amino acids to endow v-Rel with an N-terminal transactivation domain, the effect of phosphorylation on transaction by v-Rel, and the effect of C0terminal sequences on cytoplasmic localization of c-Rel. the ability of anti-apoptosis proteins in the Bcl-2 family to cooperate in v-Rel-induced oncogenesis will be investigated by creating vectors for the expression of weakly oncogenic Rel proteins and Bcl-2 family members. In a third project, the protein Trip6, which was isolated in a two-hybrid screen with v-Rel, will be characterized. Specifically, requirements for transactivation and subcellular localization of Trip6 will be explored by creating Trip6 knockout mice and cell lines. Finally, cell lines deficient in specific Rel/NF-kappaB family members will be characterized, and these cell lines will be used to analyze the contribution of specific Rel/NJ-kappaB complexes to distinct physiological processes, such as adhesion, growth control, and apoptosis. A long-term goal of this project will be to develop mammalian model systems for studying Rel-mediated oncogenesis, in order to more closely mimic human cancers that involve alterations in Rel transcription factor function.
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