Lungu Gina F, Stoica George, Wong Paul K Y
Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, USA.
J Neurovirol. 2008 May;14(3):239-51. doi: 10.1080/13550280802093919.
Moloney murine leukemia virus-temperature sensitive (MoMuLV-ts1)-mediated neuronal death is a result of both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Here the authors propose vascular endothelial growth factor (VEGF) down-regulation as another contributory factor in neuronal degeneration induced by ts1 infection. To determine how ts1 affects VEGF expression in ts1-infected brain, the authors examined the expression of several proteins that are important in regulating the expression of VEGF. The authors found significant decreases in Jun-activating domain-binding protein 1 (Jab1), hypoxia-inducible factor (HIF)-1alpha, and VEGF levels and increases in p53 protein levels in ts1-infected brains compared to noninfected control brains. The authors suggest that a decrease Jab1 expression in ts1 infection leads to accumulation of p53, which binds to HIF-1alpha to accelerate its degradation. A rapid degradation of HIF-1alpha leads to decreased VEGF production and secretion. Considering that endothelial cells are the most conspicuous in virus replication and production in ts1 infection, but are not killed by the infection, the authors examined the expression of these proteins using infected and noninfected mouse cerebrovascular endothelial (CVE) cells. The ts1- infected CVE cells showed decreased Jab1, HIF-1alpha, and VEGF mRNA and protein levels and increased p53 protein levels compared with noninfected cells, consistent with the results found in vivo. These results confirm that ts1 infection results in insufficient secretion of VEGF from endothelial cells and may result in decreased neuroprotection. This study suggested that ts1-mediated neuropathology in mice may result from changes in expression and activity of Jab1, p53, and HIF-1alpha, with a final target on VEGF expression and neuronal degeneration.
莫洛尼鼠白血病病毒温度敏感型（MoMuLV-ts1）介导的神经元死亡是神经胶质支持丧失以及ts1感染的神经胶质细胞释放细胞因子和神经毒素共同作用的结果。本文作者提出血管内皮生长因子（VEGF）下调是ts1感染诱导神经元变性的另一个促成因素。为了确定ts1如何影响ts1感染大脑中VEGF的表达，作者检测了几种在调节VEGF表达中起重要作用的蛋白质的表达。与未感染的对照大脑相比，作者发现ts1感染的大脑中Jun激活域结合蛋白1（Jab1）、缺氧诱导因子（HIF）-1α和VEGF水平显著降低，p53蛋白水平升高。作者认为，ts1感染时Jab1表达降低导致p53积累，p53与HIF-1α结合以加速其降解。HIF-1α的快速降解导致VEGF产生和分泌减少。鉴于内皮细胞在ts1感染的病毒复制和产生中最为明显，但未被感染杀死，作者使用感染和未感染的小鼠脑血管内皮（CVE）细胞检测了这些蛋白质的表达。与未感染的细胞相比，ts1感染的CVE细胞显示Jab1、HIF-1α和VEGF mRNA及蛋白水平降低，p53蛋白水平升高，这与体内研究结果一致。这些结果证实ts1感染导致内皮细胞VEGF分泌不足，可能导致神经保护作用降低。这项研究表明，ts1介导的小鼠神经病理学可能是由于Jab1、p53和HIF-1α的表达和活性变化所致，最终靶点是VEGF表达和神经元变性。
