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

B细胞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：
13671091
负责人：
HOSOKAWA Yoshitaka
金额：
$ 2.62万
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：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671091/
关键词：
Malignant lymphoma Chromosome translocation apoptosis BCL6

项目摘要

1) BCL6. The BCL-6/LAZ3 gene encodes a zinc-finger transcriptional repressor and is located at the breakpoint of the 3q27-associated translocations 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 carrying a human BCL-6 transgene that is inducible under control of the lactose operon. Using a CDNA array 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 ro … More le in the downstream of the BCL-6 signaling pathway during B - lymphoid differentiation.2) 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. Less

1) BCL6/LAZ3 基因编码锌指转录抑制因子，位于非霍奇金淋巴瘤 (NHL) 中最常发生的 3q27 相关易位的断点处，用于检查与非霍奇金淋巴瘤相关的细胞反应和靶基因。通过 BCL-6 信号通路，我们建立了携带人 BCL-6 转基因的 Ba/F3 pro-B 细胞，该转基因在乳糖的控制下可诱导使用CDNA阵列杂交技术，我们发现诱导的BCL-6蛋白可以下调细胞周期蛋白A2、趋化因子受体CXCR4和胰岛素样生长因子结合蛋白4（IGFBP-4）基因的表达。 Ba/F3细胞。Northern印迹分析证实这些基因的表达确实被诱导的BCL-6蛋白下调，但诱导的BCL-6蛋白也抑制细胞增殖。这些发现强烈表明，三个关键基因，即细胞周期蛋白 A2、CXCR4 和 IGFBP-4 可能在 B - 淋巴分化过程中的 BCL-6 信号通路下游发挥作用。2) API2 - MALT1。t(11;18)(q21;q21) 是粘膜相关淋巴组织 (MALT) 型淋巴瘤的特征性染色体易位，这种易位结果导致 API2（细胞凋亡抑制剂 2，也称为 c-IAP2）-MALT1（粘膜相关淋巴瘤易位基因 1）的嵌合转录本为了鉴定结合 API2-MALT1 嵌合蛋白的蛋白质，我们采用了免疫共沉淀和 SDS PAGE 分析，然后进行了分析。通过液相色谱-电喷雾电离串联质谱法，得到Smac、Htra2和TRAF2。免疫沉淀有力地证明，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 蛋白显着抑制了 UV 照射的 HeLa 细胞中 Smac 促进的细胞凋亡。 -MALT1 可以至少部分地通过抑制 Smac 介导的细胞凋亡途径来阻止细胞凋亡。