Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci-Bolognetti, La Sapienza University, Rome, Italy.
Oncogene. 2010 Mar 4;29(9):1316-28. doi: 10.1038/onc.2009.439. Epub 2009 Dec 7.
Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR-29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.
EB 病毒（EBV）编码的潜伏膜蛋白 1（LMP1）以其转化潜能而闻名。然而，它在伯基特淋巴瘤（BL）细胞中也具有细胞停滞和生长缓解作用。LMP1 生长抑制特性的潜在分子机制在很大程度上仍不清楚。在这项研究中，我们表明 LMP1 负调节弥漫性大 B 细胞淋巴瘤（DLBCL）和 BL 细胞中的主要癌基因 TCL1。LMP1 转染子的 microRNA（miR）谱分析表明，miR-29b 等其他 miR 上调。LMP1 通过 C 端激活区 1（CTAR1）和 CTAR2 诱导 miR-29b，从而减少 TCL1。LMP1 表达细胞中 miR-29b 锁定核酸（LNA）反义寡核苷酸转染降低了 miR-29b 的表达，从而重新构成 TCL1，表明 LMP1 通过 miR-29b 上调负调节 TCL1。LMP1 引起的 miR-29b 增加是由于人染色体 7 上 pri-miR-29b1-a 转录物的增加所致。使用药理学抑制剂，我们发现 LMP1 的 p38 丝裂原活化蛋白激酶激活功能对于这种作用很重要。LMP1 通过 miR-29b 负调节 TCL1 的能力可能是其 B 细胞淋巴瘤生长拮抗特性的基础。由于 LMP1 对 B 细胞转化也很重要，我们认为这种病毒蛋白的功能二分法可能取决于其表达水平、靶细胞的谱系和分化以及 miRs 的调节，然后指导细胞反应的结果。
