A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis.
A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis.
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作者：
Olive V;Sabio E;Bennett MJ;De Jong CS;Biton A;McGann JC;Greaney SK;Sodir NM;Zhou AY;Balakrishnan A;Foth M;Luftig MA;Goga A;Speed TP;Xuan Z;Evan GI;Wan Y;Minella AC;He L
MIR-17-92是一个强大的多顺反子癌基因，编码六个成熟的miRNAs，具有复杂的相互作用模式。在Eμ-myc Burkitt淋巴瘤模型中，Mir-17-92主要通过其miR-19组分抑制c-Myc诱导的细胞凋亡，从而显示出强大的致癌活性。令人惊讶的是，mir-17-92还编码了miR-92组件，该组件负向调节其与c-Myc的致癌合作。MiR-92的这种作用至少部分是通过直接抑制Fbw7介导的，Fbw7促进了c-Myc的蛋白体降解。因此，miR-92的过度表达导致c-Myc的异常增加，在过度增殖和P53依赖的细胞凋亡之间施加了强烈的偶联。有趣的是，miR-92拮抗致癌的miR-19 miRNAs，这种功能相互作用协调c-Myc诱导的肿瘤发生中的增殖和凋亡。这种miR-19：miR-92的拮抗作用在B淋巴瘤细胞中被破坏，B淋巴瘤细胞支持miR-19比miR-92有更大的增加。综上所述，我们提出了一种新的范式，即多顺反子oncomir的独特基因结构在癌基因和肿瘤抑制因子串扰之间提供了复杂的平衡。DOI：http://dx.doi.org/10.7554/eLife.00822.001用非常简单的话来说，基因的作用是转录成信使核糖核酸分子，然后再翻译成一连串的氨基酸，然后折叠成蛋白质。这些步骤中的每一步都极其复杂，许多其他分子可以加速、减缓、停止或以其他方式扰乱作为蛋白质产物的基因的表达。基因也可以编码不能翻译成蛋白质的核酸，比如microRNAs。这些小的RNA分子可以通过抑制翻译步骤和/或部分降解信使RNA分子来减少蛋白质的产生。MIR-17-92基因在很大程度上体现了这种复杂性。它在一个初级转录本中编码六种不同的microRNA，并与许多癌症有关，包括肺癌、伯基特淋巴瘤和其他形式的淋巴瘤和白血病。六个microRNAs中有一个的进化历史比其余五个更长：MIR-92在脊椎动物、脊索动物和无脊椎动物中发现，而另外五个只在脊椎动物中发现。然而，目前还不知道mir-17-92基因是如何或为什么进化到编码多种不同的microRNA的。Olive等人。已经研究了这些mir-17-92 microRNA如何在小鼠与Burkitt淋巴瘤的功能相互作用，Burkitt淋巴瘤是一种与一种名为c-Myc的基因过度激活有关的癌症。该基因的突变促进了细胞的增殖，与其他基因损伤协同作用，最终导致癌症。MIR-17-92与这种癌症有关，因为它抑制了人体用来阻止肿瘤生长的程序性细胞死亡(由c-Myc蛋白诱导)的过程。Olive等人。研究发现，删除六个microRNAs中的一个miR-92会增加mir-17-92基因促进Burkitt淋巴瘤的倾向。MiR-92通过抑制一种名为Fbw7的酶，导致高水平的c-Myc产生。虽然这会导致促进癌症的细胞不受控制的增殖，但它也会增加细胞程序性死亡，至少部分是通过激活众所周知的肿瘤抑制途径--p53途径。实验还表明，miR-92和另一种microRNAs miR-19的作用经常是相互对立的。这些发现揭示了单个microRNA基因内不同成分之间意想不到的相互作用，该基因在促进和抑制癌症的途径之间保持着复杂的平衡。DOI：http://dx.doi.org/10.7554/eLife.00822.002
mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk. DOI: http://dx.doi.org/10.7554/eLife.00822.001 The role of genes, in very simple terms, is to be transcribed into messenger RNA molecules, which are then translated into strings of amino acids that fold into proteins. Each of these steps is extremely complex, and a wide range of other molecules can speed up, slow down, stop or otherwise disrupt the expression of genes as protein products. Genes can also code for nucleic acids that are not translated into proteins, such as microRNAs. These are small RNA molecules that can reduce the production of proteins by repressing the translation step and/or by partially degrading the messenger RNA molecules. mir-17-92 is a gene that exemplifies much of this complexity. It codes for six different microRNAs in a single primary transcript, and has been implicated in a number of cancers, including lung cancer, Burkitt’s lymphoma and other forms of lymphomas and leukemia. One of six microRNAs has a longer evolutionary history than the remaining five: mir-92 is found in vertebrates, chordates and invertebrates, whereas the other five are only found in vertebrates. However, it is not known how or why the mir-17-92 gene evolved to code for multiple different microRNAs. Olive et al. have studied how these mir-17-92 microRNAs functionally interact in mice with Burkitt’s lymphoma, a form of cancer that is associated with a gene called c-Myc being over-activated. Mutations in this gene promote the proliferation of cells, and in cooperation with other genetic lesions, this ultimately leads to cancer. mir-17-92 is implicated in this cancer because it represses the process of programmed cell death (which is induced by the protein c-Myc) that the body employs to stop tumors growing. Olive et al. found that deleting one of the six microRNAs, miR-92, increased the tendency of the mir-17-92 gene to promote Burkitt’s lymphoma. By repressing an enzyme called Fbw7, miR-92 causes high levels of c-Myc to be produced. While this leads to the uncontrolled proliferation of cells that promotes cancer, it also increases programmed cell death, at least in part, by activating the p53 pathway, a well-known tumor suppression pathway. The experiments also revealed that the action of miR-92 and that of one of the other microRNAs, miR-19, were often opposed to each other. These findings have revealed an unexpected interaction among different components within a single microRNA gene, which acts to maintain an intricate balance between pathways that promote and suppress cancer. DOI: http://dx.doi.org/10.7554/eLife.00822.002