Abstract
BackgroundTranslation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. eIF4E, the mRNA 5′ cap-binding protein, plays a major role in translational control. To understand how eIF4E affects cell proliferation and survival, we studied mRNA targets that are translationally responsive to eIF4E.Methodology/Principal FindingsMicroarray analysis of polysomal mRNA from an eIF4E-inducible NIH 3T3 cell line was performed. Inducible expression of eIF4E resulted in increased translation of defined sets of mRNAs. Many of the mRNAs are novel targets, including those that encode large- and small-subunit ribosomal proteins and cell growth-related factors. In addition, there was augmented translation of mRNAs encoding anti-apoptotic proteins, which conferred resistance to endoplasmic reticulum-mediated apoptosis.Conclusions/SignificanceOur results shed new light on the mechanisms by which eIF4E prevents apoptosis and transforms cells. Downregulation of eIF4E and its downstream targets is a potential therapeutic option for the development of novel anti-cancer drugs.
Highlights
Post-transcriptional control of gene expression at the level of translation has emerged as an important cellular function in normal development [1] and aberrations in this process leads to diseases including cancer [2,3]
To identify mRNAs whose translation is affected by overexpression of eIF4E, an NIH 3T3 cell line overexpressing eIF4E in a tetracycline-dependent manner was used (3T3-tTA-eIF4E; [27]). eIF4E induction was readily detectable 5 hr after tetracycline removal, and eIF4E levels dramatically increased after 12 hr (Fig. 1A)
EIF4E is thought to stimulate the translation of a subset of mRNAs whose 59 untranslated regions (UTRs) contain extensive secondary structure [23]
Summary
Post-transcriptional control of gene expression at the level of translation has emerged as an important cellular function in normal development [1] and aberrations in this process leads to diseases including cancer [2,3]. A key player in the regulation of translation initiation is the mRNA 59 cap–binding protein, eIF4E, which is the limiting component of the eIF4F initiation complex. Translation deregulation is an important mechanism that causes aberrant cell growth, proliferation and survival. EIF4E, the mRNA 59 cap-binding protein, plays a major role in translational control. Inducible expression of eIF4E resulted in increased translation of defined sets of mRNAs. Many of the mRNAs are novel targets, including those that encode large- and small-subunit ribosomal proteins and cell growth-related factors. Downregulation of eIF4E and its downstream targets is a potential therapeutic option for the development of novel anti-cancer drugs
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