Eukaryotic Initiation Factor 4E-BP Protien Family: Sentinels at a Translational Checkpoint in Lung Tumor Defense. Mus musculus

The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here we show that the primary negative regulators of these oncogenic initiation factors - the 4E-BP protein family - operate as guardians of a translational control checkpoint in tumor defense. When challenged with the tobacco carcinogen NNK, 4ebp1-/-/4ebp2-/- mice showed increased sensitivity to tumorigenesis compared to their wild type counterparts. The 4E-BP deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape - with translational activation of genes governing angiogenesis, growth and proliferation; and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in tumor defense. Overall design: Comparisons of Total RNA and polysomal RNA from lungs derived from WT and 4ebp1-/-/4ebp2-/- Balb/c mice

翻译起始因子持续激活导致的翻译调控篡夺效应具有致癌性。本研究证实，这类致癌性翻译起始因子的主要负调控因子——4E-BP蛋白家族（4E-BP protein family）——可作为肿瘤防御中翻译调控检查点的守护者发挥作用。当暴露于烟草致癌物NNK时，4ebp1-/-/4ebp2-/-小鼠相较于其野生型对照小鼠，对肿瘤发生的易感性显著升高。4E-BP缺陷状态本身即可引发促致癌性的全基因组分子谱偏移：具体表现为调控血管生成、细胞生长与增殖的基因发生翻译激活，同时能够将NNK生物活化为致突变代谢物的特定细胞色素P450酶亚型CYP2A5（CYP2A5）也出现翻译激活。本研究为肿瘤防御中的翻译调控检查点提供了体内实验证据。实验设计：对比野生型（WT）与4ebp1-/-/4ebp2-/- Balb/c小鼠肺部的总RNA（Total RNA）与多聚体RNA（polysomal RNA）。