OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes.
OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes.
复制标题
DOI：
10.1371/journal.ppat.1003222
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Weitzman JB
中科院分区：
文献类型：
--
作者：
Marsolier J;Pineau S;Medjkane S;Perichon M;Yin Q;Flemington E;Weitzman MD;Weitzman JB
胞内寄生虫泰勒虫是已知的唯一能转化哺乳动物宿主细胞的真核生物。我们研究了寄生虫诱导的转化表型的宿主机制。肿瘤的进展是一个多步骤的过程，然而“癌基因成瘾”意味着癌细胞的生长和存活可以通过灭活单个基因而受损，这为靶向分子治疗提供了理论基础。此外，反馈回路通常在肿瘤发生中充当关键的调节中心。我们在感染泰勒虫的白细胞中寻找参与调节环成瘾的microRNA。我们表明泰勒虫转化涉及通过c-Jun转录因子和AP-1活性诱导宿主牛oncomiR miR-155。我们发现了一个新的miR-155靶点，DET 1，一个参与c-Jun泛素化的进化保守因子。我们发现，miR-155的表达导致DET 1蛋白的抑制，导致c-Jun的稳定，并驱动含有miR-155的BIC转录物的启动子活性。这种正反馈回路对于维持泰勒虫感染的白细胞的生长和存活至关重要;通过抑制AP-1活性或miR-155表达来逆转转化。这是第一次证明泰勒虫寄生虫诱导宿主非编码RNA的表达，并强调了一种新的反馈回路在维持寄生虫感染后诱导的增殖表型中的重要性。因此，寄生虫感染驱动宿主白细胞调节回路的表观遗传重新布线，将miR-155置于感染、调节回路和转化之间的十字路口。 泰勒虫是已知的唯一能将其宿主细胞转化为癌样状态的细胞内真核寄生虫。感染T.环纹泰勒虫引起热带泰勒虫病，在北非和亚洲杀死大量牛，相关的T。寄生虫引起东海岸热我们研究了宿主牛白细胞的转化是否与小的非编码RNA的失调有关。我们发现泰勒虫的转化导致BIC基因中包含的一种称为miR-155的致癌小RNA的上调。寄生虫对microRNA的诱导涉及控制BIC基因启动子的转录因子c-Jun的激活。我们确定了miR-155的一个新靶点;负责降解c-Jun因子的DET 1蛋白。这导致了一个调节反馈环，这对受感染细胞的转化表型至关重要。我们发现，miR-155表达抑制DET 1蛋白翻译，导致c-Jun蛋白的积累和含有miR-155的BIC基因的激活。这是第一个研究报告的调节致癌非编码RNA的泰勒虫和新的反馈回路的寄生虫诱导的转化。
The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite-induced transformation phenotypes. Tumour progression is a multistep process, yet ‘oncogene addiction’ implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c-Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation. Theileria is the only intracellular eukaryotic parasite known to transform its host cell into a cancer-like state. Infection by the T. annulata parasite causes tropical theileriosis, killing large numbers of cattle in North Africa and Asia, and the related T. parva parasite causes East Coast Fever. We investigated whether transformation of host bovine leukocytes was associated with deregulation of small, non-coding RNAs. We discovered that transformation by Theileria leads to upregulation of an oncogenic small RNA called miR-155 which is contained within the BIC gene. Parasite induction of the microRNA involves activation of the transcription factor c-Jun which controls the BIC gene promoter. We identified a new target for the miR-155; the DET1 protein which is responsible for degradation of the c-Jun factor. This leads to a regulatory feedback loop that is critical for the transformed phenotype of the infected cells. We show that miR-155 expression inhibits DET1 protein translation, leading to accumulation of c-Jun protein and activation of the BIC gene containing miR-155. This is the first study to report regulation of oncogenic non-coding RNAs by Theileria and the novel feedback loop underlying the parasite-induced transformation.
登录
查看更多内容
影响因子：
5.4
作者：
Cameron, Jennifer E.;Yin, Qinyan;Flemington, Erik K.
通讯作者：
Flemington, Erik K.
DOI：
10.1073/pnas.0703942104
发表时间：
2007-10-09
影响因子：
11.1
作者：
Gironella, Meritxell;Seux, Mylene;Dusetti, Nelson J.
通讯作者：
Dusetti, Nelson J.
影响因子：
3.6
作者：
Hayashida, Kyoko;Kajino, Kiichi;Sugimoto, Chihiro
通讯作者：
Sugimoto, Chihiro
病毒诱导的细胞微RNA miR-155在爱泼斯坦-巴氏病毒导致的B细胞不死过程中发挥关键作用
影响因子：
5.4
作者：
Linnstaedt, Sarah D.;Gottwein, Eva;Cullen, Bryan R.
通讯作者：
Cullen, Bryan R.
影响因子：
56.9
作者：
Heussler, VT;Rottenberg, S;Dobbelaere, DAE
通讯作者：
Dobbelaere, DAE