Goodman Cancer Centre and Department of Biochemistry, Cancer Pavilion, McGill University, Montreal, QC, Canada H3A 1A3.
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14134-9. doi: 10.1073/pnas.1005320107. Epub 2010 Aug 2.
Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.
翻译调控在细胞生长和增殖的控制中起着关键作用。翻译控制中的一个关键因子是eIF4E，即mRNA 5'帽结合蛋白。eIF4E的异常表达促进肿瘤发生，并与癌症的发展和进展有关。eIF4E的活性在癌症中失调。eIF4E的调控部分是通过磷酸化实现的。然而，eIF4E磷酸化在哺乳动物中的生理意义尚不清楚。在这里，我们表明，表达不可磷酸化形式eIF4E的敲入小鼠在前列腺癌模型中对肿瘤发生具有抗性。通过对翻译后的mRNA进行全基因组分析，我们表明eIF4E的磷酸化是几种与肿瘤发生相关的蛋白质翻译上调所必需的。因此，磷酸化eIF4E水平的升高与前列腺癌患者的疾病进展相关。我们的发现确立了eIF4E磷酸化是肿瘤发生中的一个关键事件。这些发现增加了这样一种可能性，即阻止eIF4E磷酸化的化合物可能用作抗癌药物。
