Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells
Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells
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EB病毒癌蛋白LMP1对鼻咽癌细胞HIF-1A表达的正向调节
DOI：
10.1016/j.canlet.2016.08.021
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发表时间：
2016-11-01
期刊：
影响因子：
9.7
通讯作者：
Lee, Jeng-Woei
中科院分区：
文献类型：
--
作者：
Sung, Wei-Wen;Chu, Yi-Chih;Lee, Jeng-Woei
潜伏膜蛋白1（LMP 1）是一种重要的病毒癌蛋白，与EB病毒（EBV）相关的恶性肿瘤（包括鼻咽癌（NPC））的发生有关。我们研究了LMP 1对缺氧诱导因子1-α（HIF-1 α）的调节作用。在NPC细胞中，我们发现LMP 1显著增强HIF-1 α mRNA水平，而不仅仅是先前描述的蛋白量。从机制上讲，HIF-1 α转录物的稳定性被LMP 1显著延长，这是通过C-末端激活区1（CTAR 1）和CTAR 3分别与ERK 1/2和STAT 3信号通路相互作用，降低RNA去稳定化蛋白tristetraprolin（TTP）和pumilio RNA结合家族成员2（pumilio RNA结合家族成员2）的表达，与HIF 2与HIF-1 α mRNA 3 ′-非翻译区（3 ′-UTR）结合的障碍平行。另一方面，HIF-1A启动子活性也明显受到LMP 1 CTAR 1募集的ERK 1/2/NF-κ B通路的促进。有趣的是，在这种情况下，增强的HIF-1a进一步表现出对其自身基因转录的积极自动调节。我们的研究结果首次表明，LMP 1直接上调HIF-1A的转录和转录后的NPC细胞，除了提供证据的HIF-1 α mRNA水平的增加引起的肿瘤相关病毒在常氧条件下。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Latent membrane protein 1 (LMP1) is a pivotal viral oncoprotein that contributes to the carcinogenesis of Epstein-Barr virus (EBV)-associated malignancies, including nasopharyngeal carcinoma (NPC). We investigated the regulation of hypoxia-inducible factor 1-alpha (HIF-1 alpha) by LMP1. In NPC cells, we found that LMP1 significantly enhanced the HIF-1 alpha mRNA level, and not only the protein amount as described previously. Mechanistically, the stability of the HIF-1 alpha transcript was remarkably prolonged by LMP1 via reduced expressions of RNA-destabilizing proteins tristetraprolin (TTP) and pumilio RNA-binding family member 2 (PUM2) through C-terminal activation region 1 (CTAR1) and CTAR3 interaction with the ERK1/2 and STAT3 signaling pathways, respectively, in parallel with hindrance of PUM2 binding to the HIF-1 alpha mRNA 3'-untranslated region (3'-UTR). On the other hand, HIF-1A promoter activity was also obviously facilitated by the LMP1 CTAR1-recruited ERK1/2/NF-kappa B pathway. Intriguingly, in this scenario, augmented HIF-1a further exhibited positive auto-regulation of its own gene transcription. Our results showed the first time that LMP1 directly up-regulates HIF-1A transcription and post-transcription in NPC cells, in addition to providing evidence of an increase in the HIF-1 alpha mRNA level caused by a tumor-associated virus under normoxic conditions. (C) 2016 Elsevier Ireland Ltd. All rights reserved.