Epstein-Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b
Epstein-Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b
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DOI：
10.1038/onc.2009.439
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发表时间：
2010-03-04
期刊：
影响因子：
8
通讯作者：
Trivedi, P.
中科院分区：
文献类型：
--
作者：
Anastasiadou, E.;Boccellato, F.;Trivedi, P.
EB病毒（EBV）编码的潜伏膜蛋白1（LMP 1）以其转化潜力而闻名。然而，它也充当伯基特淋巴瘤（BL）细胞中的细胞生长抑制因子和生长缓和因子。LMP 1的生长抑制特性的潜在分子机制在很大程度上仍然未知。在这项研究中，我们表明，LMP 1负调控的主要癌基因，TCL 1，在弥漫性大B细胞淋巴瘤（DLBCL）和BL细胞。LMP 1转染子的microRNA（miR）分析显示，其中miR-29 b上调。LMP 1通过C-末端激活区1（CTAR 1）和CTAR 2诱导miR-29 b减少TCL 1。miR-29 b锁核酸（LNA）反义寡核苷酸转染到表达LMP 1的细胞中减少了miR-29 b的表达，从而重建了TCL 1，表明LMP 1通过miR-29 b上调负调控TCL 1。LMP 1导致的miR-29 b增加是由于来自人7号染色体的簇pri-miR-29 b1-a转录的增加。使用药理学抑制剂，我们发现LMP 1的p38丝裂原活化蛋白激酶激活功能对这种作用很重要。LMP 1通过miR-29 b负调节TCL 1的能力可能是其B细胞淋巴瘤生长拮抗特性的基础。由于LMP 1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miR的调节的组合，miR然后指导细胞应答的结果。Oncogene（2010）29，1316-1328; doi：10.1038/onc.2009.439; 2009年12月7日在线发表
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. Oncogene (2010) 29, 1316-1328; doi:10.1038/onc.2009.439; published online 7 December 2009