Avian reticuloendotheliosis virus (REV-T) is the most virulent of all retroviruses inducing an invariably fatal lymphoma 7-10 days after infection. The v-rel gene arose from the transduction of a portion of the c-rel protooncogene into a replication competent retrovirus. The v-rel oncogene transforms and prevents the subsequent differentiation of T and B lymphocytes, fibroblasts and monocytes. The mechanism by which the v- Rel oncoprotein arrests differentiation and induces uncontrolled cellular proliferation is not well understood. The c-rel proto-oncogene belongs to the Rel/NF-kappa-B family of transcription factors. The members of this family share extensive sequence similarity in their N-terminal Rel homology domain (RHD). The RHD contains the DNA binding and dimerization domains as well as a nuclear translocation signal. The C-termini of Rel/NF-kappa-B family members share no sequence homology, however, they contain the elements responsible for transcriptional activation. In addition, the C-terminus of c-Rel contains a cytoplasmic retention and cytotoxic domain. Rel/NF-kappa-B complexes bind to their DNA recognition motif as dimers. Several mutations in the RHD which are important in cellular transformation are located in regions required for c-Rel to either homo- or heterodimerize with other Rel/NF-kappa-B family members. In transformed cells v-Rel exists in complexes with c-Rel, RelA, NF-kappa- B1, NF-kappa-B2, I-kappa-B-alpha and other unidentified proteins. We also have recent evidence that some members of the bZIP superfamily are associated with v-Rel in transformed cells. The overall goal of this proposal is to define the role of the other Rel/NF-kappa-B/I-kappa-B and bZIP family members in the transformation process.
The specific aims i nclude: 1. To define the composition of Rel/NF-kappa-B and bZIP complexes in the nuclei of v-Rel transformed cells. 2. To characterize the domain(s) in v-Rel that allows for association with Rel/NF-kappaB/I-kappaB family members. 3. To identify bZIP superfamily members which associate with v-Rel and characterize these interactions. 4. To determine which Rel/NF-kappaB/I-kappa-alpha and bZIP complexes contribute to v-Rel's transforming ability in fibroblasts and v-rel hematopoietic target cells.
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