Division of Collaboration and Education, Hokkaido University, Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
Exp Mol Pathol. 2013 Feb;94(1):228-38. doi: 10.1016/j.yexmp.2012.08.008. Epub 2012 Sep 7.
Our efforts are concerned with identifying features of incomplete malignant transformation caused by non viral pathogens. Theileria parva (T. parva) is a tick-transmitted protozoan parasite that can cause a fatal lymphoproliferative disease in cattle. The T. parva-infected lymphocytes display a transformed phenotype and proliferate in culture media like the other tumor cells, however those cells will return to normal after antiprotozoal treatment reflecting the incomplete nature of transformation. To identify signaling pathways involved in this form of transformation of T. parva-infected cells, we screened a library of anticancer compounds. Among these, TIBC, a specific inhibitor of MDM2, markedly inhibited proliferation of T. parva-infected lymphocytes and promoted apoptosis. Therefore we analyzed MDM2 function in T. parva-infected cells. Several T. parva-infected cell lines showed increased expression level of MDM2 with alternatively spliced isoforms compared to the lymphoma cells or ConA blasts. In addition, buparvaquone affected MDM2 expression in T. parva transformed cells. Moreover, p53 protein accumulation and function were impaired in T. parva-infected cells after cisplatin induced DNA damage despite the increased p53 transcription level. Finally, the treatment of T. parva-infected cells with boronic-chalcone derivatives TIBC restored p53 protein accumulation and induced Bax expression. These results suggest that the overexpression of MDM2 is closely linked to the inhibition of p53-dependent apoptosis of T. parva-infected lymphocytes. Aberrant expression of host lymphocyte MDM2 induced by cytoplasmic existence of T. parva, directly and/or indirectly, is associated with aspects of this type of transformation of T. parva-infected lymphocytes. This form of transformation shares features of oncogene induced malignant phenotype acquisition.
我们的研究重点是确定非病毒病原体引起的不完全恶性转化的特征。Theileria parva（T. parva）是一种蜱传原生动物寄生虫，可导致牛致命的淋巴增生性疾病。T. parva 感染的淋巴细胞表现出转化表型，并像其他肿瘤细胞一样在培养基中增殖，然而，在用抗原生动物药物治疗后，这些细胞会恢复正常，反映出转化的不完全性质。为了确定参与 T. parva 感染细胞这种转化形式的信号通路，我们筛选了抗癌化合物文库。在这些化合物中，MDM2 的特异性抑制剂 TIBC 显著抑制 T. parva 感染的淋巴细胞增殖并促进细胞凋亡。因此，我们分析了 MDM2 在 T. parva 感染细胞中的功能。与淋巴瘤细胞或 ConA 原代细胞相比，几种 T. parva 感染细胞系显示出 MDM2 表达水平增加，并且存在剪接变异体。此外，布帕伐醌影响 T. parva 转化细胞中的 MDM2 表达。此外，尽管 p53 转录水平增加，但 T. parva 感染细胞中的 cisplatin 诱导的 DNA 损伤后，p53 蛋白积累和功能受损。最后，用硼酸-查尔酮衍生物 TIBC 处理 T. parva 感染的细胞恢复了 p53 蛋白积累并诱导了 Bax 表达。这些结果表明，MDM2 的过度表达与 T. parva 感染的淋巴细胞中 p53 依赖性细胞凋亡的抑制密切相关。T. parva 细胞质存在引起的宿主淋巴细胞 MDM2 的异常表达，直接和/或间接地与 T. parva 感染的淋巴细胞这种转化形式的某些方面相关。这种转化形式具有癌基因诱导的恶性表型获得的特征。
