Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency.
Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency.
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DOI：
10.1038/nature07449
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发表时间：
2008-12-18
期刊：
影响因子：
64.8
通讯作者：
Ruggero, Davide
中科院分区：
文献类型：
--
作者：
Barna, Maria;Pusic, Aya;Zollo, Ornella;Costa, Maria;Kondrashov, Nadya;Rego, Eduardo;Rao, Pulivarthi H.;Ruggero, Davide
Myc癌基因调节蛋白质合成机制的多个组分的表达，包括核糖体蛋白、翻译起始因子、聚合酶III和核糖体DNA。一个突出的问题是，增加细胞蛋白质合成能力是否以及如何影响导致癌症的多步骤过程。我们利用核糖体蛋白杂合子小鼠作为一种遗传工具，将Eμ - Myc/+转基因小鼠中增加的蛋白质合成恢复到正常水平，并表明在这种情况下Myc的致癌潜能受到抑制。我们的研究结果表明，Myc增加蛋白质合成的能力直接增大细胞体积，并且足以独立于Myc转录调控的已知细胞周期靶点加速细胞周期进程。此外，当蛋白质合成恢复到正常水平时，Myc过表达的癌前细胞通过程序性细胞死亡更有效地被清除。我们的研究结果揭示了一种新的范式，它将致癌信号下游一般蛋白质合成速率的增加与用于调节选择性mRNA表达的翻译起始方式的特定分子损伤联系起来。我们表明，Myc过度激活下游依赖帽子结构的翻译的异常增加，特异性地损害了准确的有丝分裂进程所必需的向内部核糖体进入位点（IRES）依赖的翻译的转换。这种翻译转换的失败导致内源性IRES依赖形式的Cdk11（p58 - PITSLRE）的有丝分裂特异性表达降低，这导致胞质分裂缺陷，并与Eμ - Myc/+小鼠中中心体数量增加和基因组不稳定相关。当在Eμ - Myc/+小鼠中重新建立准确的翻译控制时，基因组不稳定被抑制。我们的研究结果揭示了翻译控制的扰动如何对基因表达、基因组稳定性和癌症起始产生高度特异性的结果，这对于在后基因组水平理解癌症形成的分子机制具有重要意义。
The Myc oncogene regulates the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III, and rDNA. An outstanding question is whether and how increasing the cellular protein synthesis capacity can affect the multi-step process leading to cancer. We utilized ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ–Myc/+ transgenic mice to normal levels and show that in this context Myc's oncogenic potential is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a novel paradigm that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation employed to regulate the expression of selective mRNAs. We show that an aberrant increase in cap-dependent translation downstream Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (p58-PITSLRE), which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ–Myc/+ mice. When accurate translational control is re-established in Eμ–Myc/+ mice, genome instability is suppressed. Our findings reveal how perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.
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影响因子：
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作者：
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通讯作者：
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