EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells
EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells
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DOI：
10.1158/0008-5472.can-06-1679
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Pagano, Joseph S.
中科院分区：
文献类型：
--
作者：
Kondo, Satoru;Seo, So Young;Pagano, Joseph S.
低氧诱导因子1（HIF 1）在大多数恶性肿瘤中上调，通常通过中断其α亚基的泛素化和蛋白酶体降解。最近，我们发现ERV的主要癌蛋白，潜伏膜蛋白1（LMP 1），激活HIF 1 α，并随后在上皮细胞中表达HIFI反应基因。在这里，我们探讨了LMP 1在鼻咽上皮细胞中激活HIF 1 α的机制：LMP 1通过增强其稳定性上调Siah 1 E3泛素连接酶的水平，随后诱导蛋白酶体降解脯氨酰HIF-羟化酶1和3，通常标记HIF 1 α降解。结果，LMP 1阻止了von Hippel-Lindau/HIF 1 α复合物的形成，如免疫共沉淀分析所示。因此，Siah 1与HIF 1 α的调节有关，并参与了最近认识到的ERV介导的肿瘤发生，即LMP 1触发的血管生成过程。
Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit alpha. Recently, we have shown that the principal ERV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1 alpha and subsequently expression of HIFI-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1 alpha activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1 alpha for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1 alpha complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1 alpha and is involved in a recently appreciated aspect of ERV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1.