Heckman C A, Duan H, Garcia P B, Boxer L M
Center for Molecular Biology in Medicine, Palo Alto VAHCS, Palo Alto, CA, USA.
Oncogene. 2006 Feb 9;25(6):888-98. doi: 10.1038/sj.onc.1209127.
Oct-1 and Oct-2 are members of the POU homeodomain family of transcriptional regulators and are critical for normal embryonic development. Gene-targeting studies showed that Oct-1 and Oct-2 are largely dispensable for B-cell development and immunoglobulin production, although both Oct-2 and Bob-1 are required for a proper immune response and germinal center formation. In these studies, we investigated the role of Oct factors in B-cell lymphomas. Recent investigations have shown increased expression of Oct-2 and Bob-1 in lymphomas, and we observed greatly increased levels of Oct-2 in lymphoma cells with the t(14;18) translocation. Decreased expression of Oct-1, Oct-2, or Bob-1 by RNA interference resulted in apoptosis and down-regulation of bcl-2 expression. Furthermore, Oct-2 induced bcl-2 promoter activity and mediated this effect through three regions in the bcl-2 P2 promoter. Although these regions did not contain canonical octamer motifs, we observed the direct interaction of Oct-2 with all three sites both in vitro by EMSA and in vivo by chromatin immunoprecipitation assay. Moreover, by mutation analysis we found that the ability of Oct-2 to activate bcl-2 required C/EBP, Cdx, and TATA-binding sites. Oct-2, therefore, acts as a cell survival factor in t(14;18) lymphoma cells by directly activating the antiapoptotic gene bcl-2.
Oct-1和Oct-2是转录调节因子POU同源结构域家族的成员，对正常胚胎发育至关重要。基因靶向研究表明，Oct-1和Oct-2在很大程度上对于B细胞发育和免疫球蛋白产生并非必需，尽管Oct-2和Bob-1对于适当的免疫反应和生发中心形成都是必需的。在这些研究中，我们调查了Oct因子在B细胞淋巴瘤中的作用。最近的研究表明淋巴瘤中Oct-2和Bob-1的表达增加，并且我们观察到具有t(14;18)易位的淋巴瘤细胞中Oct-2水平大幅增加。通过RNA干扰降低Oct-1、Oct-2或Bob-1的表达导致细胞凋亡和bcl-2表达下调。此外，Oct-2诱导bcl-2启动子活性并通过bcl-2 P2启动子中的三个区域介导这种效应。尽管这些区域不包含典型的八聚体基序，但我们通过电泳迁移率变动分析（EMSA）在体外以及通过染色质免疫沉淀测定在体内观察到Oct-2与所有三个位点的直接相互作用。此外，通过突变分析我们发现Oct-2激活bcl-2的能力需要C/EBP、Cdx和TATA结合位点。因此，Oct-2通过直接激活抗凋亡基因bcl-2在t(14;18)淋巴瘤细胞中作为细胞存活因子发挥作用。
