Carroll Patrick A, Kenerson Heidi L, Yeung Raymond S, Lagunoff Michael
Department of Microbiology, University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195, USA.
J Virol. 2006 Nov;80(21):10802-12. doi: 10.1128/JVI.00673-06. Epub 2006 Sep 6.
Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is the etiological agent of Kaposi's sarcoma, a highly vascularized, endothelial-derived tumor. A direct role for KSHV-mediated induction of angiogenesis has been proposed based upon the nature of the neoplasia and various KSHV gene overexpression and infection model systems. We have found that KSHV infection of endothelial cells induces mRNA of hypoxia-induced factor 1alpha (HIF1alpha) and HIF2alpha, two homologous alpha subunits of the heterodimeric transcription factor HIF. HIF is a master regulator of both developmental and pathological angiogenesis, composed of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit. HIF is classically activated posttranscriptionally with hypoxia, leading to increased protein stability of HIF1alpha and/or HIF2alpha. However, we demonstrate that both alpha subunits are up-regulated at the transcript level by KSHV infection. The transcriptional activation of HIF leads to a functional increase in HIF activity under normoxic conditions, as demonstrated by both luciferase reporter assay and the increased expression of vascular endothelial growth factor receptor 1 (VEGFR1), an HIF-responsive gene. KSHV infection synergizes with hypoxia mimics and induces higher expression levels of HIF1alpha and HIF2alpha protein, and HIF1alpha is increased in a significant proportion of the latently infected endothelial cells. Src family kinases are required for the activation of HIF and the downstream gene VEGFR1 by KSHV. We also show that KS lesions, in vivo, express elevated levels of HIF1alpha and HIF2alpha proteins. Thus, KSHV stimulates the HIF pathway via transcriptional up-regulation of both HIF alphas, and this activation may play a role in KS formation, localization, and progression.
卡波西肉瘤相关疱疹病毒（KSHV 或 HHV - 8）是卡波西肉瘤的病原体，卡波西肉瘤是一种血管高度丰富的、源自内皮细胞的肿瘤。基于该肿瘤的性质以及各种 KSHV 基因过表达和感染模型系统，有人提出 KSHV 介导的血管生成诱导具有直接作用。我们发现，KSHV 感染内皮细胞会诱导缺氧诱导因子 1α（HIF1α）和 HIF2α的 mRNA 表达，这两个α亚基是异二聚体转录因子 HIF 的同源亚基。HIF 是发育性和病理性血管生成的主要调节因子，由一个氧敏感的α亚基和一个组成性表达的β亚基组成。经典情况下，HIF 在转录后被缺氧激活，导致 HIF1α和/或 HIF2α的蛋白质稳定性增加。然而，我们证明，KSHV 感染会在转录水平上上调这两个α亚基。HIF 的转录激活导致在常氧条件下 HIF 活性功能性增加，这通过荧光素酶报告基因检测以及血管内皮生长因子受体 1（VEGFR1，一种 HIF 应答基因）表达增加得以证明。KSHV 感染与缺氧模拟物协同作用，诱导 HIF1α和 HIF2α蛋白表达水平更高，并且在相当比例的潜伏感染内皮细胞中 HIF1α增加。Src 家族激酶是 KSHV 激活 HIF 和下游基因 VEGFR1 所必需的。我们还表明，在体内，卡波西肉瘤病变表达的 HIF1α和 HIF2α蛋白水平升高。因此，KSHV 通过转录上调 HIF 的两个α亚基来刺激 HIF 通路，这种激活可能在卡波西肉瘤的形成、定位和进展中起作用。
