TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis
TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis
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DOI：
10.1038/onc.2015.244
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发表时间：
2016-04-07
期刊：
影响因子：
8
通讯作者：
Joubert, D.
中科院分区：
文献类型：
--
作者：
Macari, F.;El-houfi, Y.;Joubert, D.
越来越多的证据表明，蛋白质合成机制的变化改变了特定mRNA的翻译，并参与恶性转化。在这里，我们表明，蛋白激酶C α（PKC α）与TRM 6/61 tRNA甲基转移酶的催化亚基TRM 61相互作用。已知TRM 6/61复合物使起始甲硫氨酸tRNA（tRNA（i）（Met））的腺苷58甲基化，这是一种核转录后修饰，其与稳定化该抑制-起始过程的关键组分相关。TRM 6/61的缺失降低了C6胶质瘤细胞的增殖并增加了其死亡，这种效应可以通过tRNA（i）（Met）的过表达而部分地挽救。相反，升高的TRM 6/61表达调节了编码参与肿瘤发生过程的蛋白质的mRNA的子集的翻译，并且增加了C6细胞在悬浮培养时在软琼脂或球体中形成集落的能力。在TRM 6/61/tRNA（i）（Met）过表达细胞中，PKC α过表达降低了tRNA（i）（Met）表达以及集落和球体形成潜力。与II/III级胶质母细胞瘤相比，在高度侵袭性的多形性胶质母细胞瘤中检测到TRM 6/TRM 61 mRNA和tRNA（i）（Met）表达的增加以及PKC α mRNA表达的减少，这突出了我们的发现的临床意义。总之，我们认为PKC α严格控制TRM 6/61活性，以防止有利于肿瘤发展的翻译失调。
Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C alpha (PKC alpha) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNA(i)(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNA(i)(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNA(i)(Met)-overexpressing cells, PKC alpha overexpression decreased tRNA(i)(Met) expression and both colony-and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNA(i)(Met) expression with decreased expression of PKC alpha mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKC alpha tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.