| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We have demonstrated that BCAP, isolated as a binding molecule to PI3 kinase, contributes to maintenance of homeostasis of splenic mature B lymphocytes through regulation of the abundance of c-Rel, a member of the NF-κB familiy. The transcription factor NF-κB induces expression of a wide variety of genes involved in apoptosis, cell cycle and cancer metastasis. It is therefore is indispensable to clarify and manipulate signals modulating NF-κB activity toward a comprehensive understanding of onsogenesis. To this end, we set out to unravel the molecular machinery ensuring BCAP/NF-κB coupling. By using a reporter construct containing Kb-responsive elements, the C-terminal region of BCAP containing proline-rich stretches was shown to be responsible for NF-κB activation. Furthermore, BB1 was identified as a binder to this region by yeast two-hybrid screening. siRNA-mediated BB1 depletion gave rise to a drop of NF-κB activity, indicating BBl's involvement in NF-κB-modulating signals. In terms of functional domains within BB1, the Oterminal 100 amino-acid region was required for induction of NF-KB activity. To elucidate BCAP's mechanism of action in more detail, we also surveyed other signaling molecules with structural similarity, which could constitute the BCAP family, for comparison. BANK, an adaptor protein, was identified using the BLAST program. We established BANK-deficient mice and revealed that BANK negatively regulates signals via the co-receptor CD40, enabling prevention of hyper-responsiveness of B lymphocytes. Collectively, we propose that the BCAP family members operate to translate molecular events on the plasma membrane into gene induction, and serve to repress oncogenesis.
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