Functional modification of the transcription factor BCL6 by acetylation

BCL6是一种含有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通过调控下游靶基因Blimp-1、p27、MIP-1的表达来控制b细胞的发育。涉及BCL6基因的染色体易位在人b细胞淋巴瘤中经常被检测到，这表明BCL6表达的改变是淋巴瘤发生的关键事件。为了阐明BCL6的功能，我们研究了蛋白质翻译后修饰之一乙酰化的意义。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。我们还研究了BCL6表达对细胞增殖和凋亡的影响。BCL6过表达可显著抑制淋巴瘤细胞Daudi和Raji对依托泊苷等化疗药物的凋亡。BCL6过表达也受到抑制。对依托泊苷的反应是活性氧（ROS）水平的增加和线粒体跨膜电位的降低（Δψm）。活性氧清除剂n -乙酰-l-半胱氨酸（NAC）也抑制了依托opoide处理的Δψm和凋亡的减少以及活性氧水平的增加。淋巴瘤细胞。这些观察结果表明，BCL6过表达抑制化疗药物治疗淋巴瘤细胞的凋亡，很可能是通过增强抗氧化防御系统。

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.