Ambrose H E, Papadopoulou V, Beswick R W, Wagner S D
Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
Oncogene. 2007 Sep 13;26(42):6244-52. doi: 10.1038/sj.onc.1210434. Epub 2007 Apr 2.
Bcl-6 is a transcription factor that is normally expressed in germinal centre B cells. It is essential for the formation of germinal centres and the production of high-affinity antibodies. Transcriptional downregulation of Bcl-6 occurs on terminal differentiation to plasma cells. Bcl-6 is highly expressed in B-cell non-Hodgkin's lymphoma and, in a subset of cases of diffuse large cell lymphoma, the mechanism of Bcl-6 overexpression involves interruption of normal transcriptional controls. Transcriptional control of Bcl-6 is, therefore, important for normal antibody responses and lymphomagenesis, but little is known of the cis-acting control elements. This report focuses on a region of mouse/human sequence homology in the first intron of Bcl-6, which is a candidate site for such a control element. We demonstrate that poly-(ADP-ribose) polymerase-1 (Parp-1) binds in vitro and in vivo to specific sequences in this region. We further show that PARP inhibitors, and Parp-1 knockdown by siRNA induce Bcl-6 mRNA expression in Bcl-6 expressing cell lines. We speculate that Parp-1 activation plays a role in switching off Bcl-6 transcription and subsequent B-cell exit from the germinal centre.
Bcl-6是一种转录因子，通常在生发中心B细胞中表达。它对于生发中心的形成和高亲和力抗体的产生至关重要。Bcl-6的转录下调发生在向浆细胞的终末分化过程中。Bcl-6在B细胞非霍奇金淋巴瘤中高度表达，并且在一部分弥漫性大细胞淋巴瘤病例中，Bcl-6过表达的机制涉及正常转录控制的中断。因此，Bcl-6的转录控制对于正常抗体反应和淋巴瘤发生很重要，但对顺式作用控制元件知之甚少。本报告聚焦于Bcl-6第一内含子中的小鼠/人类序列同源区域，该区域是此类控制元件的候选位点。我们证明聚（ADP-核糖）聚合酶-1（Parp-1）在体外和体内均与该区域的特定序列结合。我们进一步表明，PARP抑制剂以及通过小干扰RNA敲低Parp-1可在表达Bcl-6的细胞系中诱导Bcl-6 mRNA表达。我们推测Parp-1激活在关闭Bcl-6转录以及随后B细胞从生发中心退出中发挥作用。
