Kao Chih-Fei, Chen Shiow-Yi, Chen Jeou-Yuan, Wu Lee Yan-Hwa
Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan 112, Republic of China.
Oncogene. 2004 Apr 1;23(14):2472-83. doi: 10.1038/sj.onc.1207368.
Oncogenic virus proteins often target to tumor suppressor p53 during virus life cycle. In the case of hepatitis C virus (HCV) core protein, it has been shown to affect p53-dependent transcription. Here, we further characterized the in vitro and in vivo interactions between HCV core protein and p53 and showed that these two proteins colocalized in subnuclear granular structures and the perinuclear area. By use of a reporter assay, we observed that while low level of HCV core protein enhanced the transactivational activity of p53, high level of HCV core protein inhibited this activity. In both cases, however, HCV core protein increased the p53 DNA-binding affinity in gel retardation analyses, likely due to the hyperacetylation of p53 Lys(373) and Lys(382) residues. Additionally, HCV core protein, depending on its expression level, had differential effects on the Ser(15) phosphorylation of p53. Moreover, HCV core protein could rescue p53-mediated suppressive effects on both RNA polymerase I and III transcriptions. Collectively, our results indicate that HCV core protein targets to p53 pathway via at least three means: physical interaction, modulation of p53 gene regulatory activity and post-translational modification. This feature of HCV core protein, may potentially contribute to the HCV-associated pathogenesis.
致癌病毒蛋白在病毒生命周期中常常靶向肿瘤抑制因子p53。就丙型肝炎病毒（HCV）核心蛋白而言，已证实它会影响p53依赖性转录。在此，我们进一步对HCV核心蛋白与p53之间的体外和体内相互作用进行了表征，结果显示这两种蛋白在核内亚颗粒结构和核周区域共定位。通过报告基因检测，我们观察到低水平的HCV核心蛋白增强了p53的反式激活活性，而高水平的HCV核心蛋白则抑制了这种活性。然而，在这两种情况下，凝胶阻滞分析显示HCV核心蛋白均增加了p53的DNA结合亲和力，这可能是由于p53的赖氨酸（Lys）373和赖氨酸382残基发生了高度乙酰化。此外，HCV核心蛋白根据其表达水平对p53的丝氨酸（Ser）15磷酸化具有不同影响。而且，HCV核心蛋白能够挽救p53对RNA聚合酶I和III转录的抑制作用。总体而言，我们的结果表明HCV核心蛋白至少通过三种方式靶向p53途径：物理相互作用、调节p53基因调控活性和翻译后修饰。HCV核心蛋白的这一特性可能对HCV相关的发病机制有潜在贡献。
