An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in burkitt lymphomagenesis: the Wp/BHRF1 link.
An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in burkitt lymphomagenesis: the Wp/BHRF1 link.
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DOI：
10.1371/journal.ppat.1000341
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发表时间：
2009-03
期刊：
影响因子：
6.7
通讯作者：
Rowe M
中科院分区：
文献类型：
--
作者：
Kelly GL;Long HM;Stylianou J;Thomas WA;Leese A;Bell AI;Bornkamm GW;Mautner J;Rickinson AB;Rowe M
伯基特淋巴瘤 (BL) 发病机制有两个因素，即导致 c-myc 癌基因失调的染色体易位和 Epstein-Barr 病毒 (EBV) 感染。尽管该病毒具有 B 细胞生长转化能力，但这可能与其在 BL 中的作用无关，因为许多转化蛋白在肿瘤中不表达。越来越多的证据支持另一种作用，即 EBV 抵消 c-myc 驱动的生长程序固有的高细胞凋亡敏感性。在这方面，BL 的一个子集携带病毒突变体，以一种新型的潜伏感染形式，提供异常强大的细胞凋亡抵抗力。独特的是，这些病毒突变体使用 Wp（一种通常在 B 细胞转化早期激活的病毒启动子）并表达比平常更广泛的潜在抗原。在这里，使用诱导系统表达候选抗原，我们表明这种明显的细胞凋亡抵抗不是由 Wp 限制性潜伏期中看到的扩展范围的 EBNA 介导的，而是由 Wp 驱动的病毒 bcl2 同源物 BHRF1 的表达介导的，BHRF1 是一种通常与病毒裂解周期相关的蛋白质。有趣的是，这种 Wp/BHRF1 连接并不局限于 Wp 限制性 BL，而且似乎是 EBV 正常 B 细胞转化的组成部分。我们发现最近报道的新感染 B 细胞中的 BHRF1 基因表达与 Wp 激活和 W/BHRF1 剪接转录本的存在存在时间相关。此外，正如 Wp 活性在体外转化细胞系中永远不会完全消失一样，低水平的 BHRF1 转录本在这些细胞中长期仍可检测到。最重要的是，BHRF1 特异性 T 细胞的识别证实了此类细胞系能够独立于任何裂解周期的进入而继续表达该蛋白。因此，这项工作提供了第一个证据，证明 BHRF1（EBV bcl2 同源物）在体外生长转化细胞中组成型表达为潜在蛋白，并且在 Wp 限制性 BL 的背景下，可能有助于体内病毒相关淋巴瘤的发生。癌症几乎总是通过靶细胞中几个独立变化的累积效应而发展。对于某些肿瘤，链中的一个步骤涉及用特定类型的病毒感染细胞。最好的例子是伯基特淋巴瘤 (BL)，这是一种 B 淋巴细胞肿瘤，是由于基因事故导致 c-myc 癌基因表达失控和常见疱疹病毒 Epstein-Barr 病毒 (EBV) 感染的综合作用而形成的。最近的证据表明，虽然潜伏的 EBV 感染本身可以驱动 B 细胞生长，但该病毒在 BL 中发挥着不同的作用，即抵消 c-myc 表达细胞天生较差的生存能力，同时保持其 c-myc 驱动的生长完好无损。在这里，我们证明 EBV 通过意外地开启一种病毒蛋白来实现这一目标，而这种病毒蛋白被认为在潜伏感染中永远不会被发现。这种病毒蛋白类似于细胞自身的关键生存蛋白之一，称为 bcl2。此外，这项工作使我们认识到，这种病毒编码的 bcl2 样蛋白不仅在 BL 背景下很重要，而且与传统观点相反，它实际上是 EBV B 细胞生长转化自然策略的一部分。
Two factors contribute to Burkitt lymphoma (BL) pathogenesis, a chromosomal translocation leading to c-myc oncogene deregulation and infection with Epstein-Barr virus (EBV). Although the virus has B cell growth–transforming ability, this may not relate to its role in BL since many of the transforming proteins are not expressed in the tumor. Mounting evidence supports an alternative role, whereby EBV counteracts the high apoptotic sensitivity inherent to the c-myc–driven growth program. In that regard, a subset of BLs carry virus mutants in a novel form of latent infection that provides unusually strong resistance to apoptosis. Uniquely, these virus mutants use Wp (a viral promoter normally activated early in B cell transformation) and express a broader-than-usual range of latent antigens. Here, using an inducible system to express the candidate antigens, we show that this marked apoptosis resistance is mediated not by one of the extended range of EBNAs seen in Wp-restricted latency but by Wp-driven expression of the viral bcl2 homologue, BHRF1, a protein usually associated with the virus lytic cycle. Interestingly, this Wp/BHRF1 connection is not confined to Wp-restricted BLs but appears integral to normal B cell transformation by EBV. We find that the BHRF1 gene expression recently reported in newly infected B cells is temporally linked to Wp activation and the presence of W/BHRF1-spliced transcripts. Furthermore, just as Wp activity is never completely eclipsed in in vitro–transformed lines, low-level BHRF1 transcripts remain detectable in these cells long-term. Most importantly, recognition by BHRF1-specific T cells confirms that such lines continue to express the protein independently of any lytic cycle entry. This work therefore provides the first evidence that BHRF1, the EBV bcl2 homologue, is constitutively expressed as a latent protein in growth-transformed cells in vitro and, in the context of Wp-restricted BL, may contribute to virus-associated lymphomagenesis in vivo. Cancer almost always develops through the cumulative effects of several independent changes in the target cell. For certain tumors, one step in the chain involves infection of the cell with a particular type of virus. The best example is Burkitt lymphoma (BL), a tumor of B lymphocytes which develops through the combined action of a genetic accident leading to uncontrolled expression of the c-myc oncogene and infection with a common herpesvirus, the Epstein-Barr virus (EBV). Recent evidence suggests that, although latent EBV infection can itself drive B cell growth, the virus plays a different role in the context of BL, namely to counteract the naturally poor survival ability of c-myc–expressing cells while leaving their c-myc–driven growth intact. Here we show that EBV achieves this by unexpectedly switching on a viral protein that was thought never to be seen in latent infection; this viral protein resembles one of the cell's own key survival proteins called bcl2. Furthermore, the work has led us to realise that this virally encoded bcl2-like protein is not only important in the context of BL but, contrary to conventional wisdom, is actually part of EBV's natural strategy for B cell growth transformation.
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影响因子：
9.8
作者：
Altmann, Markus;Hammerschmidt, Wolfgang
通讯作者：
Hammerschmidt, Wolfgang
影响因子：
5.4
作者：
Komano, J;Maruo, S;Takada, K
通讯作者：
Takada, K
影响因子：
82.9
作者：
Kelly, G;Bell, A;Rickinson, A
通讯作者：
Rickinson, A
DOI：
10.1016/s0006-291x(02)02261-1
发表时间：
2002-09-27
影响因子：
3.1
作者：
Kawanishi, M;Tada-Oikawa, S;Kawanishi, S
通讯作者：
Kawanishi, S
影响因子：
14.9
作者：
Bornkamm, GW;Berens, C;Feuillard, J
通讯作者：
Feuillard, J