Eif4e haploinsufficiency is compatible with development but impairs oncogenic transformation.
Major finding: Eif4e haploinsufficiency is compatible with development but impairs oncogenic transformation.
Mechanism: eIF4E controls an oncogenic translation program that includes mRNAs important for ROS regulation.
Impact: Targeting eIF4E-dependent oncogenic translation may increase sensitivity to ROS induction.
The major cap binding protein eukaryotic initiation factor 4E (eIF4E) is thought to represent the limiting factor for mRNA translation efficiency. However, the dose of eIF4E required for normal development and for global and specific mRNA translation remains unknown. Truitt, Conn, and colleagues addressed this question by generating mice heterozygous for Eif4e (Eif4e+/−), which developed normally and showed no defect in global protein synthesis. However, when challenged with an oncogenic insult, Eif4e+/− mouse embryonic fibroblasts (MEF) were resistant to cellular transformation compared with their wild-type counterparts. Unbiased translational profiling identified genes translationally induced by oncogenic transformation in an eIF4E-dependent manner, including a subset of genes involved in reactive oxygen species (ROS) regulation and the response to oxidative stress. The 5′ untranslated region of many of these mRNAs contained a 15-nucleotide cis-acting motif, termed the cytosine-enriched regulator of translation domain, which was enriched in eIF4E targets induced upon oncogenic transformation and required for eIF4E-selective translation of target mRNAs. Transformed Eif4e+/− cells exhibited increased intracellular ROS levels associated with enhanced induction of apoptosis, supporting the requirement of eIF4E to promote the growth and survival of cancer cells by controlling ROS levels. Depletion of specific eIF4E target mRNAs in wild-type cells reduced transformation efficiency, whereas treatment of Eif4e+/− cells with ROS scavengers rescued their tumorigenic potential. Consistent with these findings, Eif4e haploinsufficiency increased oxidative stress, reduced tumor burden, and sensitized tumors to pharmacologic ROS induction in a KRAS-driven lung cancer model. Together, these data support the hypothesis that cancer cells require physiologic levels of eIF4E to selectively translate mRNAs necessary to control escalating ROS levels. Furthermore, this phenomenon reveals a potential therapeutic window in which the eIF4E-dependent translational program might be targeted to manipulate ROS levels in cancer cells.
Truitt ML, Conn CS, Shi Z, Pang X, Tokuyasu T, Coady AM, et al. Differential requirements for eIF4E dose in normal development and cancer. Cell 2015;162:59–71.
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