Functional modification of the transcription factor BCL6 by acetylation

通过乙酰化对转录因子 BCL6 进行功能修饰

• 批准号: 14570966
• 负责人: MIKI Tohru
• 金额: $ 2.24万
• 依托单位: TOKYO MEDEICAL AND DENTAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570966/
• 关键词: Malignant Lymphoma; BCL6; Acetylation; Transcription Factor; 転写抑制因子; zinc-finger protein; BAZ F

BCL6, a transcriptional repressor containing zinc-finger domain, is preferentially expressed in germinal-center B-cells. BCL6 controls B-cell development through regulating expression of down-stream target genes including Blimp-1, p27 and MIP-1. Chromosomal translocation involving BCL6 gene is frequently detected in human B-cell lymphomas, suggesting alteration of BCL6 expression is crucial event in lymphomagenesis. To clarify the function of BCL6, we investigated the significance of acetylation, one of post-translational modifications of proteins. We found that BCL6 interacts with histone acetyl-transferase p300 through mid-portion of BCL6, and acetylated by p300. Transcriptional repression activity of BCL6 was remarkably reduced by acetylation. BCL6 also interacted with P/CAF histone acetyl-transferase.We also examined the effects of BCL6 expression on cell proliferation and apoptosis. BCL6 overexpression significantly inhibited apoptosis of lymphoma cells Daudi and, Raji, in response to etoposide and other chemotherapeutic reagents. BCL6 overexpression also inhibited. the increase in reactive oxygen species (ROS) levels and the reduction of mitochondria transmembrane potential (Δψm) in response to etoposide. The ROS scavenger N-acetyl-l-cysteine (NAC) also inhibited the reduction of Δψm and apoptosis as well as the increase in ROS levels in etoposide-treated. lymphoma cells. These observations indicate that BCL6 overexpression inhibits apoptosis of lymphoma cens treated with chemotherapeutic reagents, most likely through enhancement of the antioxidant defense system.

Bcl6是一种含锌指结构域的转录抑制因子，在生发中心B细胞中优先表达。Bcl6通过调节下游靶基因Blimp-1、p27和MIP-1的表达来调控B细胞的发育。涉及bcl6基因的染色体易位在人类B细胞淋巴瘤中经常被检测到，提示bcl6表达的改变在淋巴瘤的发生中起重要作用。为了阐明BCL6的功能，我们研究了乙酰化的意义，这是蛋白质的翻译后修饰之一。我们发现BCL6通过BCL6的中间部分与组蛋白乙酰转移酶p300相互作用，并被p300乙酰化。乙酰化显著降低了BCL6的转录抑制活性。Bcl6还与P/Caf组蛋白乙酰转移酶相互作用。我们还检测了bcl6的表达对细胞增殖和凋亡的影响。Bcl6过表达可显著抑制Daudi和Raji淋巴瘤细胞对依托泊苷等化疗药物的诱导作用。Bcl6的过表达也受到抑制。依托泊苷可使线粒体跨膜电位(Δψm)降低，活性氧(ROS)水平升高。ROS清除剂N-乙酰-L-半胱氨酸也能抑制依托泊苷处理后Δψm的降低和细胞凋亡率的降低以及ROS水平的升高。淋巴瘤细胞。这些观察表明，BCL6过表达抑制了化疗药物治疗的淋巴瘤细胞的凋亡，很可能是通过增强抗氧化防御系统实现的。

项目成果

BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells

• DOI: 10.1038/sj.onc.1206755
• 发表时间: 2003-07-17
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Kurosu, T;Fukuda, T;Miura, O
• 通讯作者: Miura, O

Kurosu T, Fukuda T, Miki T, Miura O.: "BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells"Oncogene. 22・29. 4459-4468 (2003)

Kurosu T、Fukuda T、Miki T、Miura O.：“BCL6 过度表达可防止 B 细胞淋巴瘤细胞中活性氧的增加并抑制化疗试剂诱导的细胞凋亡”Oncogene 22·29 (2003)。

Sakashita C, Fukuda T, Okabe S, Kobayashi H, Hirosawa S, Tokuhisa T, Miyasaka N, Miura O, Miki T: "Cloning and characterization of the human BAZF gene, a homologue of the BCL6 oncogene"Oncogene. 291(3). 567-573 (2002)

Sakashita C、Fukuda T、Okabe S、Kobayashi H、Hirosawa S、Tokuhisa T、Miyasaka N、Miura O、Miki T：“人类 BAZF 基因（BCL6 癌基因的同源物）的克隆和表征”癌基因。