Mohan Joanne, Dement-Brown Jessica, Maier Sabine, Ise Tomoko, Kempkes Bettina, Tolnay Mate
Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA.
Blood. 2006 Jun 1;107(11):4433-9. doi: 10.1182/blood-2005-09-3815. Epub 2006 Jan 26.
Fc-receptor homolog 5 (FcRH5) is a recently identified B-cell membrane protein of unknown function. In Burkitt lymphoma cell lines with chromosome 1q21 abnormalities, FcRH5 expression is deregulated, implicating FcRH5 in lymphomagenesis. Epstein-Barr virus infects and immortalizes B cells, and is implicated in the etiology of several tumors of B-cell origin. Overexpression of genes located on 1q21-25 has been proposed as a surrogate for Epstein-Barr virus in Burkitt lymphoma. We now report that Epstein-Barr virus nuclear antigen 2 (EBNA2) markedly induces the expression of the FcRH5 gene, encoded on chromosome 1q21. Induction occurred in the absence of other viral proteins and did not require de novo protein synthesis. EBNA2 lacks a DNA-binding domain and can target responsive genes through the host DNA binding protein CBF1. We show that induction of FcRH5 by EBNA2 is strictly CBF1 dependent, as it was abolished in CBF1-deficient cells. Accordingly, EBNA2 targeted CBF1 binding sites present in the FcRH5 promoter in vivo, as detected by chromatin immunoprecipitation. These results identify FcRH5 as a novel, direct target of EBNA2 that may contribute to the development of Epstein-Barr virus-associated tumors.
Fc受体同源物5（FcRH5）是一种最近发现的功能未知的B细胞膜蛋白。在具有1q21染色体异常的伯基特淋巴瘤细胞系中，FcRH5的表达失调，提示FcRH5参与淋巴瘤的发生。爱泼斯坦-巴尔病毒感染B细胞并使其永生化，且与几种B细胞起源肿瘤的病因有关。位于1q21 - 25的基因过表达已被认为是伯基特淋巴瘤中爱泼斯坦-巴尔病毒的替代指标。我们现在报告，爱泼斯坦-巴尔病毒核抗原2（EBNA2）显著诱导位于1q21染色体上的FcRH5基因的表达。诱导在没有其他病毒蛋白的情况下发生，且不需要从头合成蛋白质。EBNA2缺乏DNA结合结构域，可通过宿主DNA结合蛋白CBF1靶向反应性基因。我们表明，EBNA2对FcRH5的诱导严格依赖于CBF1，因为在CBF1缺陷细胞中这种诱导作用消失。因此，通过染色质免疫沉淀检测发现，EBNA2在体内靶向FcRH5启动子中存在的CBF1结合位点。这些结果确定FcRH5是EBNA2的一个新的直接靶点，可能有助于爱泼斯坦-巴尔病毒相关肿瘤的发展。
