The transforming v-rel gene-containing retrovirus causes multiple lymphomas in infected young chicken within 7-10 days. The v-rel oncogene and its cellular homologue, c-rel, belong to the Rel/NF-kappaB family proteins that control the transcription of many viral and cellular genes including HIV-l and lymphokines. The goal of the proposed research is (i) to identify novel c-Rel-interacting factors, and (ii) to characterize at the molecular level how mutations can alter dimerization spectrum and function of c-Rel. These specific questions will be addressed: l. How c-Rel transduces mitogenic signals? We will clone novel c-Rel- interacting factors by the expression cloning method or the two-hybrid system. The identities of these factors will provide insightful information about the molecules that transduce mitogenic signals to and from c-Rel. 2. What mutations change the dimerization spectrum of c-Rel? What dimerizations are important for c-Rel function? We will generate c-Rel mutant library by random mutagenesis. The two-hybrid system, a genetic method for detecting protein interactions, will be used to screen mutant library. We will identify the mutants that are defective in either homo- or hetero-dimerization. Transcriptional activities of these mutants will be examined to identify the protein interactions that are important for c- Rel action. 3. What signal transduction pathways require c-Rel? We will construct the dominant-negative mutants that specifically inhibit c-Rel function. They will be used to prove the c-Rel involvement in various T-cell activation pathways. In total, these studies will assess systematically the significance of different protein-protein interactions in c-Rel function. This will also provide parallel understanding of other Rel/NF-kappaB family of transcription factors. The information gained in these studies will be important in our understanding of signal transduction pathways and oncogenesis mediated by c-Rel. It also will be of value in the future design of therapeutic agents for AIDS and other immunological disorders.
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