The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers in relation to disease progression and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Enhanced eIF4E function results from eIF4E overexpression and/or activation of the ras and phosphatidylinositol 3-kinase/AKT pathways and selectively increases the translation of key mRNAs involved in tumor growth, angiogenesis, and cell survival. Consequently, by simultaneously and selectively reducing the expression of numerous potent growth and survival factors critical for malignancy, targeting eIF4E for inhibition may provide an attractive therapy for many different tumor types. Recent work has now shown the plausibility of therapeutically targeting eIF4E and has resulted in the advance of the first eIF4E-specific therapy to clinical trials. These studies illustrate the increased susceptibility of tumor tissues to eIF4E inhibition and support the notion that the enhanced eIF4E function common to many tumor types may represent an Achilles' heel for cancer.
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"At this step, mRNA is recruited to the ribosome by the eukaryotic translation initiation factor 4F (eIF4F) complex, which consists of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A (Jackson et al., 2010). Although eIF4E is required for cap-dependent translation of all nuclear transcribed cellular mRNAs, it preferentially stimulates the translation of a subset of ''eIF4E-sensitive'' mRNAs, which includes mRNAs encoding proliferation-and survival-promoting proteins (Graff et al., 2008). The sensitivity of mRNA to eIF4E can be dictated by the structure and sequence of its 5 0 untranslated region (5 0 UTR) (Hsieh et al., 2012; Koromilas et al., 1992; Thoreen et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Translational control plays a pivotal role in the regulation of the pluripotency network in embryonic stem cells, but its effect on reprogramming somatic cells to pluripotency has not been explored. Here, we show that eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs), which are translational repressors, have a multifaceted effect on the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs). Loss of 4E-BP expression attenuates the induction of iPSCs at least in part through increased translation of p21, a known inhibitor of somatic cell reprogramming. However, MEFs lacking both p53 and 4E-BPs show greatly enhanced reprogramming resulting from a combination of reduced p21 transcription and enhanced translation of endogenous mRNAs such as Sox2 and Myc and can be reprogrammed through the expression of only exogenous Oct4. Thus, 4E-BPs exert both positive and negative effects on reprogramming, highlighting the key role that translational control plays in regulating this process.
"This is in line with data showing that JNK2 is the major JNK protein that is constitutively activated in glioblastoma. JNK2 was also shown to support tumourigenesis in vivo by activating Akt and up-regulating the expression of eukaryotic translation initiation factor 4 (Cui et al., 2006), which is frequently overexpressed in many human cancers (Graff et al., 2008). More recent evidence indicates a role for JNKs in maintaining glioma stem cell properties, which are responsible for the poor prognosis of glioblastoma patients. "
[Show abstract][Hide abstract] ABSTRACT: The c-Jun NH2-terminal kinases (JNKs) are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs are involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumor suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and more importantly what effect small molecule inhibitors of JNKs have on physiological processes are an absolute must. A number of ATP-competitive and ATP-noncompetitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and hematological malignancies and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.
Preview · Article · Sep 2013 · British Journal of Pharmacology
"eIF4E also interacts with the scaffold protein eIF4G to recruit other translation factors and the 40S ribosomal subunit to the mRNA, to facilitate efficient initiation of mRNA translation. eIF4E is strongly implicated in events that lead to tumorigenesis; e.g., levels of eIF4E are elevated in many cancers (reviewed  ) and artificial overexpression of eIF4E in mammalian cells  or in animal models leads to transformation or accelerated tumorigenesis  . This may be because increasing the levels of available eIF4E favours the translation or nucleocytoplasmic transport of certain mRNAs, whose products promote cell proliferation or survival . "
[Show abstract][Hide abstract] ABSTRACT: Eukaryotic initiation factor eIF4E and its phosphorylation play key roles in cell transformation and tumorigenesis. eIF4E is phosphorylated by the Mnks (MAP (mitogen-activated protein) kinase-interacting kinases). Rapamycin increases eIF4E phosphorylation in cancer cells, potentially limiting their anti-cancer effects. Here we show that the rapamycin-induced increase in eIF4E phosphorylation reflects increased activity of Mnk2 but not Mnk1. This activation requires a novel phosphorylation site in Mnk2a, Ser437. Our findings have potentially important implications for the use of rapamycin and its analogues in cancer therapy, suggesting that inhibitors of mTOR and Mnk (or Mnk2) may be more efficacious than rapalogs alone.