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Study for the mechanism of lymphocyte development by Bach2 transcription factor and clinical analysis of Bach2 gene

Bach2转录因子淋巴细胞发育机制研究及Bach2基因临床分析

基本信息

批准号：
12670721
负责人：
ITO Etsuro
金额：
$ 2.3万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670721/
关键词：
Bach2 cnc family B cell transcription factor cncファミリー

项目摘要

The transcription factors Bach1 and Bach2, members of the BTB-basic region leucine zipper (bZip) factor family, bind to a 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element and the related Maf-recognition element (MARE) by forming homodimers or heterodirners with Maf-related transcription factors. Among human hematopoietic cell lines (12 myeloid cell lines and 16 lymphocytic cell lines), BACH2 is expressed abundantly only in some B-lymphocytic cell lines. Enforced expression of BACH2 in a human Burkitt cell line, RAJI that does not express endogenous BACH2, resulted in marked reduction of clonogenic activity, indicating that BACH2 possesses an inhibitory effect on cell proliferation. A large-scale comparison of the expression profiles between a human B cell line without endogenous BACH2 expression and a BACH2-overexpressing subline, using two-color fluorescence hybridization of cDNA microarray, led to the identification of Bcl-2 homologue A1 with anti-apoptotic activity and … More EBI3 which is a homologue to IL-12 (p40) as target genes of Bach2. A1 and EBI3 were expressed in all human B-cell lines which do not express BACH2. However, no expression was detected in B-cell lines expressing BACH2. Luciferase reporter and gel retardation assays revealed the responsive elements in the 5' region of the human A1 gene. Hence Bach2 might be involved in repression of A1 gene at earlier stages of B-cell differentiation and control of B-cell apoptosis.By fluorescent in situ hybridization, the BACH2 gene was localized to chromosome 6q15. Because deletion of the long arm of chromosome 6 (6q) is one of the commonest chromosomal alterations in human B-cell lymphoma, we examined for the loss of heterozygosity (LOH) of the BACH2 gene in human B-cell non-Hodgkin's lymphomas (NHL). Among 25 informative cases, 5 (20 %) showed LOH. To analyze the mutations of BACH2 gene in these lymphomas, we examine the structure of the BACH2 gene and determined the sequences of the all coding exons and the exon-intron boundaries. By direct sequence analysis, no mutations were detected in the f lymphoma samples with the LOH of BACH2 gene. These results indicate that BACH2 plays important roles irregulation of B cell proliferation, although it remains still elusive whether loss of BACH2 function is involved in B-cell tumorigenesis Less

转录因子Bach 1和Bach 2是BTB-碱性区亮氨酸拉链（bZip）因子家族的成员，通过与Maf相关转录因子形成同源二聚体或异源二聚体而与12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）-响应元件和相关Maf-识别元件（MARE）结合。在人造血细胞系（12种骨髓细胞系和16种淋巴细胞系）中，BACH 2仅在一些B淋巴细胞系中大量表达。在不表达内源性BACH 2的人Burkitt细胞系RAJI中BACH 2的强制表达导致克隆形成活性显著降低，表明BACH 2对细胞增殖具有抑制作用。使用cDNA微阵列的双色荧光杂交，对没有内源性BACH 2表达的人B细胞系和BACH 2过表达亚系之间的表达谱进行了大规模比较，鉴定出具有抗凋亡活性的Bcl-2同源物A1， ...更多信息 EBI 3是IL-12（p40）的同源物，作为Bach 2的靶基因。A1和EBI 3在所有不表达BACH 2的人B细胞系中表达。然而，在表达BACH 2的B细胞系中未检测到表达。荧光素酶报告基因和凝胶阻滞分析揭示了人A1基因5'区的反应元件。荧光原位杂交结果表明，Bach 2基因定位于染色体6 q15，其表达产物与A1基因的表达和B细胞凋亡有关。由于6号染色体长臂（6 q）缺失是人类B细胞淋巴瘤中最常见的染色体变异之一，我们检测了人类B细胞非霍奇金淋巴瘤（NHL）中BACH 2基因的杂合性缺失（洛）。在25例有信息的病例中，5例（20%）出现洛合性缺失。为了分析BACH 2基因在这些淋巴瘤中的突变，我们检测了BACH 2基因的结构，并确定了所有编码外显子的序列和外显子-内含子边界。直接序列分析结果显示，BACH 2基因洛缺失的淋巴瘤组织中未发现突变。这些结果表明，BACH 2在B细胞增殖的不调控中起重要作用，尽管BACH 2功能的丧失是否涉及B细胞肿瘤发生仍然是一个谜。