Both v-Rel and c-Rel belong to the Rel/NFkappaB family of transcription factors, that have been implicated in the control of cell differentiation and proliferation. The members of this family share extensive sequence similarity in their N-terminal Rel homology region, activate the transcription of genes linked to kappaB DNA motifs and exhibit related biological activities. The study of cell transformation by v-Rel provides a good model system to understand how Rel proteins normally function in lymphoid cells and how their aberrant activity leads to lymphoid cell malignancies. The ability of v-Rel to competitively inhibit transcription by its cellular homolog c-Rel and endogenous NFkappaB factors, combined with the recent mapping of a new transcription activation domain in v-Rel that is absolutely required for cell transformation, suggests that v-Rel and rearranged cellular Rel proteins may disrupt normal cell differentiation and proliferation by altering the expression of critical cellular genes, leading to lymphomagenesis. Given the important role of Rel proteins in lymphoid cells and the consequences associated with their malfunction, it is important to elucidate the mechanisms by which they operate and to understand the molecular basis for their regulation. Previous findings support the involvement of the transcriptional activities of v-Rel and c-Rel in their biological function and point to their regulation by nuclear IkappaB factors. Experiments are proposed to characterize the transcriptional activities of v-Rel and c-Rel with respect to their biological function (Aim 1), and to study their regulation by nuclear IkappaB factors (Aim 2) and by phosphorylation (Aim 3). These studies will help to clarify the pathways through which this important family of regulators functions in normal and malignant lymphoid cells.
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