Epstein-Barr virus LMP2A interferes with global transcription factor regulation when expressed during B-lymphocyte development
Epstein-Barr virus LMP2A interferes with global transcription factor regulation when expressed during B-lymphocyte development
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DOI：
10.1128/jvi.77.1.105-114.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Longnecker, R
中科院分区：
文献类型：
--
作者：
Portis, T;Longnecker, R
eb病毒（EBV）与免疫功能低下个体的恶性淋巴瘤和淋巴增生性疾病的发展有关。EBV的LMP2A蛋白被认为在这一过程中发挥核心作用，允许病毒在潜伏感染的B淋巴细胞中持续存在。我们已经证明，当LMP2A在转基因小鼠的B细胞中表达时，可以绕过正常的B细胞发育检查点。为了确定参与这一过程的LMP2A靶向细胞基因，我们利用DNA微阵列比较了野生型和LMP2A转基因小鼠B细胞中的基因转录。在LMP2A转基因小鼠的B细胞中，我们观察到许多与正常B细胞发育相关的基因表达减少，以及调节其表达的转录因子水平降低。特别是，骨髓和脾B细胞中转录因子E2A的表达下调。此外，E2A活性在这些细胞中被抑制，这是通过DNA结合减少和其靶基因表达减少来确定的，包括转录因子早期b细胞因子和Pax-5。在表达LMP2A的脾B细胞中，两种E2A抑制剂Id2和SCL的表达上调，提示E2A抑制的可能机制。这些结果表明，LMP2A在发育中的B细胞中调节转录因子的表达和活性，这可能允许绕过正常的B细胞发育所需的正常信号事件。LMP2A干扰b细胞转录因子调节的能力对其在EBV潜伏期中的作用具有重要意义。
Epstein-Barr virus (EBV) is associated with the development of malignant lymphomas and lymphoproliferative disorders in immunocompromised individuals. The LMP2A protein of EBV is thought to play a central role in this process by allowing the virus to persist in latently infected B lymphocytes. We have demonstrated that LMP2A, when expressed in B cells of transgenic mice, allows normal B-cell developmental checkpoints to be bypassed. To identify cellular-genes targeted by LMP2A that are involved in this process, we have utilized DNA microarrays to compare gene transcription in B cells from wild-type versus LMP2A transgenic mice. In B cells from LMP2A transgenic mice, we observed decreased expression of many genes associated with normal B-cell development as well as reduced levels of the transcription factors that regulate their expression. In particular, expression of the transcription factor E2A was down-regulated in bone marrow and splenic B cells. Furthermore, E2A activity was inhibited in these cells as determined by decreased DNA binding and reduced expression of its target genes, including the transcription factors early B-cell factor and Pax-5. Expression of two E2A inhibitors, Id2 and SCL, was up-regulated in splenic B cells expressing LMP2A, suggesting a possible mechanism for E2A inhibition. These results indicate that LMP2A deregulates transcription factor expression and activity in developing B cells, and this likely allows for a bypass of normal signaling events required for proper B-cell development. The ability of LMP2A to interfere with B-cell transcription factor regulation has important implications regarding its role in EBV latency.