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Analysis of regulation of carcinogenesis by the BCAP-binding molecule BB1

BCAP结合分子BB1对致癌作用的调控分析

基本信息

批准号：
17590263
负责人：
YAMAZAKI Tetsuo
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590263/
关键词：
cancer signal transduction gene regulation of expression cell・tissue

项目摘要

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.

我们已经证明，BCAP作为PI3激酶的结合分子，通过调节NF-κB家族成员c-Rel的丰度，有助于维持脾成熟B淋巴细胞的动态平衡。转录因子NF-κB可诱导多种与细胞凋亡、细胞周期和肿瘤转移相关的基因表达。因此，阐明和操纵调节NF-κB活性的信号对于全面理解肿瘤发生是必不可少的。为此，我们着手揭开确保BCAP/NF-κB偶联的分子机制。通过使用包含KB响应元件的报告结构，BCAP的C-末端区域包含富含Pro的延伸部分，被证明负责NF-κB的激活。此外，通过酵母双杂交筛选，BB1被鉴定为该区域的结合蛋白。SiRNA介导的Bb1缺失导致了NF-κB活性的下降，表明bbl参与了NF-κB的信号调节。在BB1内的功能结构域方面，O末端100氨基酸区域是诱导核因子-KB活性所必需的。为了更详细地阐明BCAP的作用机制，我们还对其他结构相似的信号分子进行了比较，这些分子可能构成BCAP家族。BLAST程序鉴定了BANK，这是一种连接蛋白。我们建立了BANK缺陷小鼠，发现BANK通过共受体CD40负向调节信号，从而能够防止B淋巴细胞的高反应性。总之，我们认为BCAP家族成员的作用是将质膜上的分子事件转化为基因诱导，并起到抑制肿瘤发生的作用。