Acetylation inactivates the transcriptional repressor BCL6
Acetylation inactivates the transcriptional repressor BCL6
复制标题
DOI：
10.1038/ng1018
复制
发表时间：
2002-12-01
期刊：
影响因子：
30.8
通讯作者：
Dalla-Favera, R
中科院分区：
文献类型：
--
作者：
Bereshchenko, OR;Gu, W;Dalla-Favera, R
原癌基因BCL 6编码BTB/POZ-锌指转录抑制因子，其是生殖中心形成所必需的，并且与B细胞淋巴瘤的发病机制有关。在这里，我们表明，共激活蛋白p300结合和乙酰化BCL 6在体内，并抑制其功能。乙酰化破坏BCL 6募集组蛋白脱乙酰酶（HDAC）的能力，从而阻碍其抑制转录和诱导细胞转化的能力。BCL 6在生理条件下在正常生殖中心B细胞和生殖中心衍生的B细胞肿瘤中被乙酰化。用特异性抑制剂治疗显示BCL 6的乙酰化水平受HDAC依赖性和SIR 2依赖性途径两者控制。这些途径的药理学抑制导致无活性的乙酰化BCL 6的积累以及B细胞淋巴瘤细胞中的细胞周期停滞和细胞凋亡。这些结果确定了一个新的机制，调节原癌基因BCL 6与潜在的治疗开发。此外，这些发现提供了一种新的机制，乙酰化不仅可以通过修饰组蛋白和激活转录激活因子来促进转录，还可以通过抑制转录抑制因子来促进转录。
The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is necessary for germinal-center formation and has been implicated in the pathogenesis of B-cell lymphomas. Here we show that the coactivator p300 binds and acetylates BCL6 in vivo and inhibits its function. Acetylation disrupts the ability of BCL6 to recruit histone deacetylases (HDACs), thereby hindering its capacity to repress transcription and to induce cell transformation. BCL6 is acetylated under physiologic conditions in normal germinal-center B cells and in germinal center-derived B-cell tumors. Treatment with specific inhibitors shows that levels of acetylation of BCL6 are controlled by both HDAC-dependent and SIR2-dependent pathways. Pharmacological inhibition of these pathways leads to the accumulation of the inactive acetylated BCL6 and to cell-cycle arrest and apoptosis in B-cell lymphoma cells. These results identify a new mechanism of regulation of the proto-oncogene BCL6 with potential for therapeutic exploitation. Furthermore, these findings provide a new mechanism by which acetylation can promote transcription not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.