Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.
Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.
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DOI：
10.1158/0008-5472.can-14-2789
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发表时间：
2015-01-15
期刊：
影响因子：
11.2
通讯作者：
Sonenberg N
中科院分区：
文献类型：
--
作者：
Pelletier J;Graff J;Ruggero D;Sonenberg N
升高的蛋白质合成是许多癌细胞的重要特征，并且通常是由于引导至真核起始因子（eIF）4F（翻译起始的mRNA-核糖体募集阶段的关键调节因子）的信号通量增加而出现。在许多癌症的细胞和临床前模型中，eIF 4F失调导致特定mRNA类别的翻译效率变化。重要的是，这些mRNA中的许多编码蛋白质，这些蛋白质有效地调节关键的细胞过程，例如细胞生长和增殖、增强的细胞存活和细胞迁移，这些过程最终影响癌症的几个标志，包括增加的血管生成、失调的生长控制、增强的细胞存活、上皮向间充质转化、侵袭和转移。通过定位为关键致癌信号传导途径（例如Ras、PI 3 K/AKT/TOR和Myc）下游的分子联系，eIF 4F充当癌症发展和翻译起始中的重要步骤之间的直接联系。鉴定出对eIF 4F活性升高（代表肿瘤发生）特别敏感的mRNA，强调了eIF 4F在癌症中的关键作用，并提出了开发新型靶向翻译起始的小分子作为抗肿瘤药物的可能性。
Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor (eIF) 4F, the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and pre-clinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes such as cell growth and proliferation, enhanced cell survival, and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g. Ras, PI3K/AKT/TOR, and Myc), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as anti-neoplastic agents.