Phan Ryan T, Dalla-Favera Riccardo
Institute for Cancer Genetics and the Department of Pathology, Columbia University, New York, New York 10032, USA.
Nature. 2004 Dec 2;432(7017):635-9. doi: 10.1038/nature03147.
The human proto-oncogene BCL6 encodes a BTB/POZ-zinc-finger transcriptional repressor that is necessary for germinal-centre formation and is implicated in the pathogenesis of B-cell lymphoma. The precise function of BCL6 in germinal-centre development and lymphomagenesis is unclear because very few direct BCL6 target genes have been identified. Here we report that BCL6 suppresses the expression of the p53 (also known as tp53) tumour suppressor gene and modulates DNA damage-induced apoptotic responses in germinal-centre B cells. BCL6 represses p53 transcription by binding two specific DNA sites within the p53 promoter region and, accordingly, p53 expression is absent in germinal-centre B cells where BCL6 is highly expressed. Suppression of BCL6 expression via specific short interfering RNA leads to increased levels of p53 messenger RNA and protein both under basal conditions and in response to DNA damage. Most notably, constitutive expression of BCL6 protects B cell lines from apoptosis induced by DNA damage. These results suggest that an important function of BCL6 is to allow germinal-centre B cells to tolerate the physiological DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. These findings also imply that deregulated BCL6 expression contributes to lymphomagenesis in part by functional inactivation of p53.
人类原癌基因BCL6编码一种BTB/POZ-锌指转录抑制因子，它是生发中心形成所必需的，并且与B细胞淋巴瘤的发病机制有关。由于很少有直接的BCL6靶基因被鉴定出来，因此BCL6在生发中心发育和淋巴瘤发生中的精确功能尚不清楚。在此，我们报告BCL6抑制p53（也称为tp53）肿瘤抑制基因的表达，并调节生发中心B细胞中DNA损伤诱导的凋亡反应。BCL6通过结合p53启动子区域内的两个特定DNA位点来抑制p53转录，因此，在BCL6高表达的生发中心B细胞中不存在p53表达。通过特异性短干扰RNA抑制BCL6表达会导致在基础条件下以及对DNA损伤作出反应时p53信使RNA和蛋白质水平升高。最值得注意的是，BCL6的组成型表达可保护B细胞系免受DNA损伤诱导的凋亡。这些结果表明，BCL6的一个重要功能是使生发中心B细胞能够耐受免疫球蛋白类别转换重组和体细胞超突变所需的生理性DNA断裂，而不诱导p53依赖性凋亡反应。这些发现还意味着BCL6表达失调部分通过p53的功能失活促成淋巴瘤发生。
