NF-kB comprises an important group of transcription factors, found in virtually all mammalian cell types, that regulate numerous genes containing specific """"""""kB"""""""" sites. These include at least two proto-oncogenes (MYC and MYB) and genes encoding cytokines, immunoreceptors, and adhesion molecules. A broad variety of agents, including mitogens, cytokines, and environmental stresses, induce NF-kB activity. It has a key role in immune responses and is required for proliferation of B- and T-lymphocytes in response to most mitogenic signals. """"""""IkB"""""""" proteins inhibit NF-kB by sequestering it in the cytoplasm or by inhibiting its DNA-binding activity. They identified an atypical member of the IkB family, encoded by the BCL3 gene, through its involvement in a 14;19 translocation found in some patients with chronic lymphocytic leukemia (CLL). Like other IkBs, it binds to certain NF-kB factors, but, rather than inhibiting, it activates transcription through two distinct mechanisms. It can act either as an antirepressor or as a coactivator; in the latter case, it forms a ternary complex with DNA and NF-kB in which transactivation domains on BCL3 stimulate transcription. The proposed work centers on the hypothesis that BCL3 provides an alternative mode of transcriptional activation of critical kB-regulated genes. To test the hypothesis that overexpression of BCL3 aberrantly activates kB-dependent genes and thereby contributes to leukemogenesis, they generated five lines of transgenic mice that overexpress BCL3 in their lymphocytes. They will determine whether the mice develop overt neoplasia or expansion of the B-cell population or have other lymphocytic abnormalities, including altered expression of genes regulated by NF-kB. So far, they have found frequent lymphadenopathy and a consistent increase in the fraction of lymph node B-cells. They will test three additional, mechanistic hypotheses based on the results so far: 1) that BCL3 binding influences the DNA-sequence specificity of NF-kB proteins; 2) that protein-protein interactions influence BCL3's ability to form ternary complexes with NF-kB proteins and DNA; and 3) that phosphorylation enhances its ability to function as a coactivator, but decreases its antirepressor activity. NF-kB proteins regulate a remarkably wide variety of genes that direct key biological processes. Their involvement in so many pathways raises the question of how specificity is conferred. They propose that BCL3, as the only IkB protein known to activate transcription, has a particularly important role in selective activation of a subset of critical kB-regulated genes. The proposed experiments are all directed at testing this hypothesis.
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