Disease relevance of EIF4E

• The relationship between angiogenesis and eukaryotic translation initiation factor 4E (EIF4E) expression level in non-Hodgkin lymphoma (NHL) was studied [1].
• The results showed that: (1) The Expression of EIF4E and MVD was higher in aggressive lymphomas than in indolent lymphomas (P < 0.05)and the expression of EIF4E was positively correlated with MVD in lymph node of NHL (r = 0.695, P < 0.01) [1].
• Adenovirus is shown to prevent cellular translation by displacing Mnk1 from eIF4F, thereby blocking phosphorylation of eIF4E [2].
• We extended our studies to provide the first evidence that the nuclear transport function of eIF4E contributes to human malignancy, specifically in a subset of acute and chronic myelogenous leukemia patients [3].
• A 49-amino-acid region of eIF-4 gamma, located in the N-terminal side of the site of cleavage by Picornaviridae protease 2A, was found to be sufficient for interacting with eIF-4E [4].

Psychiatry related information on EIF4E

• In the current study, we found a dramatic increase of phosphorylated eIF4E in Alzheimer's disease, especially in those cases with late stages of neurofibrillary changes [5].

High impact information on EIF4E

• While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells [6].
• Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation [6].
• We used antibody to the nuclear cap binding protein CBP80 or its cytoplasmic counterpart eIF4E to immunopurify RNP containing nonsense-free or nonsense-containing transcripts [7].
• Discrimination between cellular and late Ad mRNAs and inhibition of host protein synthesis are shown to involve viral-mediated underphosphorylation of cap-binding protein (CBP) and subsequent inactivation of CBP complex, a large enzymatic complex required for cap-dependent mRNA translation [8].
• This review will summarise recent findings on the MAP kinase signalling pathway that leads to phosphorylation of eIF4E and on pathways that regulate repression of eIF4E function [9].

Chemical compound and disease context of EIF4E

• Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway [10].
• Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride [11].
• Growth inhibition of head and neck squamous carcinoma cells by small interfering RNAs targeting eIF4E or cyclin D1 alone or combined with cisplatin [12].
• Ribavirin potently suppresses eIF4E-mediated oncogenic transformation of murine cells in vitro, of tumor growth of a mouse model of eIF4E-dependent human squamous cell carcinoma in vivo, and of colony formation of eIF4E-dependent acute myelogenous leukemia cells derived from human patients [13].
• Modulation of eIF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells [14].

Biological context of EIF4E

• Assignment of the human gene encoding eukaryotic initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4 [15].
• Antisense EIF4E cDNA was cloned into plasmid pcDNA3 [1].
• However, recent studies of nonsense-mediated mRNA decay (NMD) indicate that cap-binding protein (CBP)80-bound mRNA, which is a precursor to eIF4E-bound mRNA, can also be translated during a pioneer round of translation [16].
• These results explain the specific inhibition of cap-dependent translation in mitosis and also explain how eIF4E is rendered hypophosphorylated during mitosis [17].
• It is the least abundant component of the translation initiation machinery and its activity is modulated by phosphorylation and interaction with eIF4E-binding proteins (4E-BPs) [18].

Anatomical context of EIF4E

• Mean microvessel density (MVD) and EIF4E were detected in 52 lymph node samples paraffin sections of patients with newly diagnosed NHL by the way of immunohistochemistry [1].
• Polysome profiles indicate that CBP80-bound mRNAs are translated less efficiently than their eIF4E-bound counterparts [16].
• Phosphorylation of the repressor decreases its affinity for eIF-4E, and thus relieves translational inhibition. eIF-4E forms a complex with two other polypeptides, eIF-4A and p220, that promote 40S ribosome binding to mRNA [19].
• Emx2 axonal localization, association with high-density particles and interaction with eIF4E strongly suggest that this transcription factor has new nonnuclear functions most probably related to the local control of protein translation in the olfactory sensory neuron axons [20].
• Here we show that Maskin undergoes several phosphorylation events during oocyte maturation, some of which are important for its dissociation from eIF4E and translational activation of CPE-containing mRNA [21].

Associations of EIF4E with chemical compounds

• Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells [22].
• Consistently, overexpression of a series of PML and eIF4E mutant proteins established that PML eIF4E interaction is required for the observed effects of cadmium and interferon treatment [23].
• Mutation of these sites to alanine alleviates the cdk1-induced dissociation of Maskin from eIF4E [21].
• Exposure of human cell lines, HCT15, PLC/PR/5, HeLa, and Chang, to cadmium chloride resulted in cytotoxicity and cell death, and this was associated with a significant decrease in eIF4E protein levels [11].
• VSV infection of HeLa cells resulted in the dephosphorylation of eIF4E at serine 209 between 3 and 6 h postinfection [24].
• These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K [25].

Physical interactions of EIF4E

• Furthermore, we demonstrate that 4E-BP1 competes with p220 for binding to eIF-4E [19].
• We demonstrate that eukaryotic initiation factor 4E (eIF4E) directly binds the PML RING, a domain required for association with bodies and for suppression of transformation [26].
• In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state [27].
• Backbone resonance assignment of human eukaryotic translation initiation factor 4E (eIF4E) in complex with 7-methylguanosine diphosphate (m7GDP) and a 17-amino acid peptide derived from human eIF4GII [28].
• We demonstrate that eIF4E requires cap binding for transport of Cyclin D1 mRNA and subsequent transformation activity [26].

Enzymatic interactions of EIF4E

• The homology is most striking in the middle region of the protein, which contains the eIF4E binding motif and residues that are phosphorylated in 4E-BP1 [29].
• Over expression of an eIF4E mutant that cannot be phosphorylated by Mnk1 impairs translation of cellular but not viral late mRNAs [2].
• Protein kinase C-related kinase 2 phosphorylates the protein synthesis initiation factor eIF4E in starfish oocytes [30].
• Casein kinase I phosphorylates the 25-kDa mRNA cap-binding protein [31].

Regulatory relationships of EIF4E

• PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA [26].
• Through this interaction, PRH inhibits eIF4E-dependent mRNA transport and subsequent transformation [32].
• The activity of eIF4E is thought to be regulated by interaction with inhibitory binding proteins (4E-BPs) and phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress [33].
• Interaction of Mnk1 with eIF4G promotes the phosphorylation of eIF4E [34].
• In cultured cells, eIF-4E facilitates cell cycle progression by increasing the expression of cell cycle promoting proteins including cyclin D1 [35].

Other interactions of EIF4E

• Consequently, eIF4E is sequestered from the eIF4G/Mnk1 complex [17].
• Thus, translational control by growth factors, insulin and mitogens is affected by changes in the relative affinities of 4E-BP1 and p220 for eIF-4E [19].
• Further more, PML RING modulates eIF4E activity by drastically reducing its affinity for its substrate, 5' m(7)G cap of mRNA [26].
• By using CGP 57380, a novel low-molecular-weight kinase inhibitor of MNK1, we demonstrate that eIF4E phosphorylation is not crucial to the formation of the initiation complex, mitogen-stimulated increase in cap-dependent translation, and cell proliferation [33].
• Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels [36].

Analytical, diagnostic and therapeutic context of EIF4E

• Western blot analysis also showed that the protein levels of the three eIFs were differentially increased. eIF-4A protein levels increased in proportion to the observed increase in cellular protein synthetic activity while the increases in eIF-4E and eIF-2 alpha proteins were proportionately less [37].
• In addition, we have localized a second eIF-4E gene (EIF4EL2, eukaryotic translation initiation factor 4E-like 2) to human chromosome 20 by Southern blot analysis of mapping panels established from human/rodent somatic cell hybrids [38].
• We also analyzed the expression of eIF-2a in the same samples as this factor is usually regulated similarly to eIF-4E in cell culture models [35].
• Patients overexpressing eIF4E had significantly worse overall (P = 0.01) and disease-free survival (P = 0.006) [39].
• High-resolution X-ray crystallography and complementary biophysical methods have revealed that this eIF4E recognition motif undergoes a disorder-to-order transition, adopting an L-shaped, extended chain/alpha-helical conformation when it interacts with a phylogenetically invariant portion of the convex surface of eIF4E [40].

References