MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes
MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes
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DOI：
10.1016/j.yexmp.2012.08.008
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发表时间：
2013-02-01
影响因子：
3.6
通讯作者：
Sugimoto, Chihiro
中科院分区：
文献类型：
--
作者：
Hayashida, Kyoko;Kajino, Kiichi;Sugimoto, Chihiro
我们的努力是关于识别特征的不完全恶性转化引起的非病毒性病原体。细小弧菌（T. parva）是一种蜱传播的原生动物寄生虫，可在牛中引起致命的淋巴增生性疾病。细小t病毒感染的淋巴细胞表现出转化的表型，并像其他肿瘤细胞一样在培养基中增殖，但这些细胞在经过原虫治疗后会恢复正常，这反映了转化的不完全性质。为了确定参与微小t感染细胞这种形式转化的信号通路，我们筛选了一个抗癌化合物库。其中，MDM2特异性抑制剂TIBC可显著抑制细小t感染淋巴细胞的增殖，促进细胞凋亡。因此，我们分析了MDM2在细小绦虫感染细胞中的功能。与淋巴瘤细胞或ConA原细胞相比，一些细小t病毒感染的细胞系显示MDM2的表达水平增加。此外，布帕伐酮还影响了微小t细胞中MDM2的表达。此外，顺铂诱导的DNA损伤后，细小t虫感染细胞中p53蛋白的积累和功能受损，尽管p53转录水平升高。最后，用硼-查尔酮衍生物TIBC处理细小绦虫感染的细胞，恢复p53蛋白的积累，诱导Bax的表达。这些结果表明，MDM2的过表达与parva感染淋巴细胞p53依赖性凋亡的抑制密切相关。细小绦虫细胞质存在诱导宿主淋巴细胞MDM2的异常表达，直接和/或间接地与细小绦虫感染淋巴细胞的这种转化有关。这种形式的转化具有致癌基因诱导的恶性表型获得的特征。(C) 2012爱思唯尔公司版权所有。
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. (C) 2012 Elsevier Inc. All rights reserved.