BASIC STUDIES ON A TRANSCRIPTION FACTOR NF-κB AND SIGNAL TRANSDUCTION THERAPY

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NF-κB controls gene expression of a number of genes and is recently found to be involved in suppression of apoptosis. NF-κB exerts its biological actions through interacting with other cellular proteins. In order to identify molecular partners, we have applied the yeast two-hybrid screening with portions of NF-κB p65 subunit (RelA) as "baits". We have isolated a new gene, called RelA-associated inhibitor (RAI), which have subsequently shown to be located in the nucleus and block the NF-κB -mediated gene expression by inhibiting its DNA binding. Thus, RAI appears to act as a fail-safe mechanism to ensure the silencing of NF-κB or as a feed-back system to downregulate NF-κB activity. Using a different portion of p65 as a "bait", we have identified AES and TLE1, that are the members of Groucho family proteins known as transcriptional co-repressors of Drosophila homologue of human RelA, Dorsal. We have demonstrated that human AES/TLE1 also blocks NF-κB -mediated transcription Since NF-κB has recently been found to be involved in the morphogenesis of higher multicellular organisms, it is expected that human Groucho homologue may be involved in the human body plan in association with NF-κB although the exact mechanism and dynamics should further be explored. Finally, we have identified 53BP2, initially identified as an interacting molecular partner of a tumor suppressor p53 protein, as an interacting protein with p65. When 53BP2 is transduced into cells, these cells were killed with the characteristic features suggesting apoptosis such as fragmented and condensed nuclei and annexin V staining. interestingly, when p65 gene is cotransfected with 53BP2, the 53BP2-induced cell death was completely blocked. These findings suggest that interaction of p65 with 53BP2 may explain, at least in a part, how NF-κB and p65 (RelA) blocks apoptosis.