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Molecular analysis of malignant lymphoma-related oncogenes and its clinical application for diagnosis and treatment.

恶性淋巴瘤相关癌基因的分子分析及其临床诊断和治疗应用。

基本信息

批准号：
15591034
负责人：
HOSOKAWA Yoshitaka
金额：
$ 2.24万
依托单位：
Aichi Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591034/
关键词：
Malignant lymphoma apoptosis Chromosome translocation プロテオミックス NF-κB

项目摘要

1)API2-MALT1. t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue(MALT) type lymphoma, and this translocation results in chimeric transcript of API2(APoptosis Inhibitor 2,also known as c-IAP2)-MALT1(Mucosa-Associated Lymphoma Translocation gene 1). To identify proteins that bind API2-MALT1 chimeric protein, we employed coimmunoprecipitation and SDS PAGE analysis, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, Smac, Htra2,and TRAF2 were identified as API2-MALT1-binding proteins. Immunoprecipitation analysis demonstrated that ectopically expressed API2-MALT1 protein indeed binds to these endogeneous proteins. Furthermore, API2-MALT1 protein significantly inhibited Smac-promoted apoptosis in UV irradiated HeLa cells. These data strongly suggest that API2-MALT1 can block apoptosis, at least in part, by inhibiting Smac-mediated apoptotic pathway.2)BCL6. The BCL-6/LAZ3 gene encodes a zinc-finge … More r transcriptional represser and is located at the breakpoint of the 3q27-associated translations that occur most frequently in non-Hodgkin's lymphomas (NHLs To examine cell responses and target genes related to the BCL-6 signaling pathway, we established Ba/F3 pro-B cells carrrying a human BCL-6 transgene that is inducible under control of the lactose operon. Using a cDNAarray hybridization technique, we found that the induced BCL-6 protein can downregulate the expressions of the genes, cyclin A2. chemokine receptor CXCR4,and insulin-like growth factor binding protein-4(IGFBP-4) in the Ba/F3 cells. Northern blot analysis established that the expressions of these genes were indeed downregulated by the induced BCL-6 protein but in a somewhat different manner. The induced BCL-6 protein also inhibited cell proliferation of Ba/F3 cells. These findings strongly suggest that three key genes, namely cyclin A2,CXCR4 and IGFBP-4 may play a role in the downstream of the BCL-6 signaling pathway during B-lymphoid differentiation. Less

1)API2-MALT1。T(11；18)(q21；q21)是黏膜相关淋巴组织(MALT)型淋巴瘤的一种特征性染色体易位，这种易位导致API2(又称c-IAP2)-MALT1(黏膜相关淋巴瘤易位基因1)的嵌合转录本。为了鉴定与API2-MALT1嵌合蛋白结合的蛋白质，我们采用免疫共沉淀和十二烷基硫酸钠-电喷雾串联质谱仪进行分析。结果Smac、Htra2和TRAF2被鉴定为API2-MALT1结合蛋白。免疫沉淀分析表明异位表达的API2-MALT1蛋白确实与这些内源性蛋白结合。此外，API2-MALT1蛋白显著抑制Smac诱导的紫外线照射的HeLa细胞的凋亡。这些数据有力地表明，API2-MALT1至少部分地通过抑制Smac介导的凋亡途径来阻断细胞凋亡。Bcl6/laz3基因编码锌指…更多的r转录抑制因子，位于非霍奇金淋巴瘤(NHL)中最常见的3q27相关翻译的断裂点。为了检测细胞反应和与bcl6信号通路相关的靶基因，我们建立了携带人bcl6转基因的BA/F3Pro-B细胞，该基因在乳糖操纵子的控制下可被诱导。利用cDNA阵列杂交技术，我们发现诱导的bcl6蛋白可以下调细胞周期蛋白A2基因的表达。趋化因子受体CXCR4和胰岛素样生长因子结合蛋白4(IGFBP-4)在BA/F3细胞中的表达。Northern印迹分析证实，这些基因的表达确实被诱导的bcl6蛋白下调，但方式略有不同。诱导的bcl6蛋白也抑制了BaF3细胞的增殖。这些发现有力地表明，三个关键基因，即细胞周期蛋白A2、CXCR4和IGFBP-4可能在B淋巴系分化过程中的bcl6信号通路下游发挥作用。较少