Larsson Ola, Perlman David M, Fan Danhua, Reilly Cavan S, Peterson Mark, Dahlgren Cecilia, Liang Zicai, Li Shunan, Polunovsky Vitaly A, Wahlestedt Claes, Bitterman Peter B
Department of Medicine, University of Minnesota, MMC 276, Minneapolis, MN 55455, USA.
Nucleic Acids Res. 2006;34(16):4375-86. doi: 10.1093/nar/gkl558. Epub 2006 Aug 26.
Aberrant activation of the translation initiation machinery is a common property of malignant cells, and is essential for breast carcinoma cells to manifest a malignant phenotype. How does sustained activation of the rate limiting step in protein synthesis so fundamentally alter a cell? In this report, we test the post transcriptional operon theory as a possible mechanism, employing a model system in which apoptosis resistance is conferred on NIH 3T3 cells by ectopic expression of eIF4E. We show (i) there is a set of 255 transcripts that manifest an increase in translational efficiency during eIF4E-mediated escape from apoptosis; (ii) there is a novel prototype 55 nt RNA consensus hairpin structure that is overrepresented in the 5'-untranslated region of translationally activated transcripts; (iii) the identified consensus hairpin structure is sufficient to target a reporter mRNA for translational activation under pro-apoptotic stress, but only when eIF4E is deregulated; and (iv) that osteopontin, one of the translationally activated transcripts harboring the identified consensus hairpin structure functions as one mediator of the apoptosis resistance seen in our model. Our findings offer genome-wide insights into the mechanism of eIF4E-mediated apoptosis resistance and provide a paradigm for the systematic study of posttranscriptional control in normal biology and disease.
翻译起始机制的异常激活是恶性细胞的一个共同特性，对于乳腺癌细胞表现出恶性表型至关重要。蛋白质合成限速步骤的持续激活是如何从根本上改变细胞的呢？在本报告中，我们测试转录后操纵子理论作为一种可能的机制，采用一个模型系统，其中通过异位表达eIF4E赋予NIH 3T3细胞抗凋亡能力。我们发现：（i）有一组255个转录本在eIF4E介导的逃避凋亡过程中表现出翻译效率增加；（ii）有一种新的55 nt RNA共有发夹结构在翻译激活转录本的5'非翻译区中过度富集；（iii）所鉴定的共有发夹结构足以在促凋亡应激下将报告mRNA靶向翻译激活，但仅在eIF4E失调时；以及（iv）骨桥蛋白，一种带有所鉴定共有发夹结构的翻译激活转录本，在我们的模型中作为抗凋亡的一种介质发挥作用。我们的研究结果提供了全基因组范围内对eIF4E介导的抗凋亡机制的见解，并为正常生物学和疾病中转录后调控的系统研究提供了一个范例。
