Okada Y, Sawa H, Tanaka S, Takada A, Suzuki S, Hasegawa H, Umemura T, Fujisawa J, Tanaka Y, Hall W W, Nagashima K
Laboratory of Molecular & Cellular Pathology, School of Medicine and Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, CREST, Japan.
J Biol Chem. 2000 Jun 2;275(22):17016-23. doi: 10.1074/jbc.275.22.17016.
Polyomavirus JC (JCV) causes the human demyelinating disease, progressive multifocal leukoencephalopathy (PML). The recent demonstration of cases of PML in association with human T-lymphotropic virus type I (HTLV-I) infection prompted us to examine whether the HTLV-I-encoded regulatory protein Tax activates JCV transcription. By employing a dual luciferase assay, we initially found that the expression of Tax activated the transcriptional potential of both early and late promoters of JCV in human neuronal but not in non-neuronal cells. We subsequently analyzed the mechanism of Tax-induced activation of the JCV promoter in neuronal cells with the following results: 1) the JCV promoter that lacks the NF-kappaB-binding motif could not be activated by Tax; 2) the overexpression of IkappaBalpha abolished Tax-induced transcriptional activation of the JCV promoter; 3) a Tax mutant (M22) lacking the potential for activation via the NF-kappaB pathway did not activate the JCV promoter. Furthermore, Tax enhances the gene expression of JCV T antigen and VP1. We examined mechanisms of the cell-specific activation of the JCV promoter by Tax. Electrophoretic mobility shift assay demonstrated the presence of Tax-bound protein(s) that were specifically present in non-neuronal cells. This study is the first demonstration of the activation of JCV promoter by HTLV-I Tax in an NF-kappaB-dependent manner.
多瘤病毒 JC（JCV）可引发人类脱髓鞘疾病——进行性多灶性白质脑病（PML）。近期有证据表明 PML 病例与人类 I 型嗜 T 淋巴细胞病毒（HTLV-I）感染有关，这促使我们研究 HTLV-I 编码的调节蛋白 Tax 是否能激活 JCV 转录。通过采用双荧光素酶测定法，我们最初发现 Tax 的表达在人类神经元细胞而非非神经元细胞中激活了 JCV 早期和晚期启动子的转录潜能。随后，我们分析了 Tax 在神经元细胞中诱导激活 JCV 启动子的机制，结果如下：1）缺乏 NF-κB 结合基序的 JCV 启动子不能被 Tax 激活；2）IκBα 的过表达消除了 Tax 诱导的 JCV 启动子转录激活；3）缺乏通过 NF-κB 途径激活潜能的 Tax 突变体（M22）未激活 JCV 启动子。此外，Tax 增强了 JCV T 抗原和 VP1 的基因表达。我们研究了 Tax 对 JCV 启动子进行细胞特异性激活的机制。电泳迁移率变动分析表明，在非神经元细胞中特异性存在与 Tax 结合的蛋白质。本研究首次证明 HTLV-I Tax 以 NF-κB 依赖的方式激活 JCV 启动子。
