Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1α
Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1α
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DOI：
10.1128/mcb.24.12.5223-5234.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Pagano, JS
中科院分区：
文献类型：
--
作者：
Wakisaka, N;Kondo, S;Pagano, JS
低氧诱导因子-1(HIF-1)是一种由HIF-1α和HIF-1β组成的异二聚体碱性螺旋-环-螺旋转录因子，是缺氧反应的中枢调节因子。HIF-1与低氧反应元件(HRE)的特异性结合诱导低氧反应基因的转录，包括血管内皮生长因子(VEGF)。在这里，我们报告了在不同的EB病毒(EBV)感染的II型和III型细胞系中HIF-1α的表达增加，这些细胞系表达EBV潜伏膜蛋白1(EBV的主要癌蛋白)以及其他潜伏蛋白，但在EBV阴性的亲代细胞系中不表达。首先，我们发现，将LMP1表达载体导入EB病毒阴性的鼻咽上皮细胞株Ad-AH细胞，可诱导HIF-1α蛋白的合成，但不会增加其稳定性或mRNA水平。丝裂原活化蛋白激酶(MAPK)激酶抑制剂PD98059显著降低LMP1对HIF-1α的诱导。过氧化氢酶是一种过氧化氢清除剂，强烈抑制LMP1诱导的过氧化氢的产生，导致LMP1诱导的HIF-1α表达下降。抑制核因子-kappaB、c-jun氨基末端激酶、p38MAPK和磷脂酰肌醇3-激酶通路并不影响HIF-1α的表达。此外，LMP1还可诱导HIF-1 DNA结合活性，上调HRE和VEGF启动子的转录活性。最后，LMP1可增加细胞外液中VEGF蛋白的表达，而PD98059或过氧化氢酶可抑制其诱导表达。这些结果表明，LMP1通过诱导HIF-1α蛋白表达而增加HIF-1活性，该作用受p42/p44 MAPK活性和H_2O_2控制。EBV，特别是其主要癌蛋白LMP1，与先前报道的其他侵袭性和血管生成因子一起诱导HIF-1α的能力揭示了这种肿瘤病毒的额外致癌特性。
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta that is the central regulator of responses to hypoxia. The specific binding of HIF-1 to the hypoxia-responsive element (HRE) induces the transcription of genes that respond to hypoxic conditions, including vascular endothelial growth factor (VEGF). Here we report that expression of HIF-1alpha is increased in diverse Epstein-Barr virus (EBV)-infected type II and III cell lines, which express EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein, as well as other latency proteins, but not in the parental EBV-negative cell lines. We show first that transfection of an LMP1 expression plasmid into Ad-AH cells, an EBV-negative nasopharyngeal epithelial cell line, induces synthesis of HIF-1alpha protein without increasing its stability or mRNA level. The mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 markedly reduces induction of HIF-1alpha by LMP1. Catalase, an H2O2 scavenger, strongly suppresses LMP1-induced production of H2O2, which results in a decrease in the expression of HIF-1alpha induced by LMP1. Inhibition of the NF-kappaB, c-jun N-terminal kinase, p38 MAPK, and phosphatidylinositol 3-kinase pathways did not affect HIF-1alpha expression. Moreover, LMP1 induces HIF-1 DNA binding activity and upregulates HRE and VEGF promoter transcriptional activity. Finally, LMP1 increases the appearance of VEGF protein in extracellular fluids; induction of VEGF is suppressed by PD98059 or catalase. These results suggest that LMP1 increases HIF-1 activity through induction of HIF-1alpha protein expression, which is controlled by p42/p44 MAPK activity and H2O2. The ability of EBV, and specifically its major oncoprotein, LMP1, to induce HIF-1alpha along with other invasiveness and angiogenic factors reported previously discloses additional oncogenic properties of this tumor virus.