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是包含锌指域的转录表示，优选在生发中心B细胞中表达。 Bcl6通过调节下游靶基因在内的调节（包括Blimp-1，p27和MIP-1）来控制B细胞的发育。在人B细胞淋巴瘤中经常检测到涉及BCl6基因的染色体易位，这表明BCL6表达的改变是淋巴细胞化的关键事件。为了阐明BCl6的功能，我们研究了乙酰化的重要性，乙酰化是蛋白质后翻译后修饰之一。我们发现Bcl6与BCl6中期至中期与组蛋白乙酰基转移酶P300相互作用，并通过p300进行乙酰化。通过乙酰化可显着降低Bcl6的转录表达活性。 BCl6还与P/CAF组蛋白乙酰基转移酶相互作用。我们还检查了Bcl6表达对细胞增殖和凋亡的影响。 Bcl6的过表达显着抑制了Daudi和Raji的淋巴瘤细胞凋亡，以响应依托泊苷和其他化学治疗试剂。 Bcl6的过表达也抑制了。活性氧水平（ROS）水平的增加以及线粒体跨膜电位（Δψm）的降低对依托泊苷的响应。 ROS清除剂N-乙酰基L-半胱氨酸（NAC）也抑制了Δψm和凋亡的还原以及依托泊苷处理的ROS水平的增加。淋巴瘤细胞。这些观察结果表明，Bcl6的过表达抑制了用化学治疗试剂治疗的淋巴瘤凋亡的凋亡，这很可能是通过增强抗氧化剂防御系统的。

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。