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Gene Review

EIF4E  -  eukaryotic translation initiation factor 4E

Homo sapiens

Synonyms: AUTS19, CBP, EIF4E1, EIF4EL1, EIF4F, ...
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Disease relevance of EIF4E


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


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


Regulatory relationships of EIF4E


Other interactions of EIF4E


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].


  1. Relationship between eukaryotic translation initiation factor 4E and malignant angiogenesis in non-Hodgkin lymphoma. Zhao, Y., Liu, W., Zhou, S., Zhou, J., Sun, H. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. (2005) [Pubmed]
  2. Adenovirus-specific translation by displacement of kinase Mnk1 from cap-initiation complex eIF4F. Cuesta, R., Xi, Q., Schneider, R.J. EMBO J. (2000) [Pubmed]
  3. Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Topisirovic, I., Guzman, M.L., McConnell, M.J., Licht, J.D., Culjkovic, B., Neering, S.J., Jordan, C.T., Borden, K.L. Mol. Cell. Biol. (2003) [Pubmed]
  4. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mader, S., Lee, H., Pause, A., Sonenberg, N. Mol. Cell. Biol. (1995) [Pubmed]
  5. Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain. Li, X., An, W.L., Alafuzoff, I., Soininen, H., Winblad, B., Pei, J.J. Neuroreport (2004) [Pubmed]
  6. Small-Molecule Inhibition of the Interaction between the Translation Initiation Factors eIF4E and eIF4G. Moerke, N.J., Aktas, H., Chen, H., Cantel, S., Reibarkh, M.Y., Fahmy, A., Gross, J.D., Degterev, A., Yuan, J., Chorev, M., Halperin, J.A., Wagner, G. Cell (2007) [Pubmed]
  7. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Ishigaki, Y., Li, X., Serin, G., Maquat, L.E. Cell (2001) [Pubmed]
  8. Adenovirus inhibition of cellular protein synthesis involves inactivation of cap-binding protein. Huang, J.T., Schneider, R.J. Cell (1991) [Pubmed]
  9. The mRNA 5' cap-binding protein eIF4E and control of cell growth. Sonenberg, N., Gingras, A.C. Curr. Opin. Cell Biol. (1998) [Pubmed]
  10. 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. Pervin, S., Singh, R., Hernandez, E., Wu, G., Chaudhuri, G. Cancer Res. (2007) [Pubmed]
  11. Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride. Othumpangat, S., Kashon, M., Joseph, P. J. Biol. Chem. (2005) [Pubmed]
  12. Growth inhibition of head and neck squamous carcinoma cells by small interfering RNAs targeting eIF4E or cyclin D1 alone or combined with cisplatin. Oridate, N., Kim, H.J., Xu, X., Lotan, R. Cancer Biol. Ther. (2005) [Pubmed]
  13. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L., Borden, K.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  14. Pifithrin-{alpha} Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes. Wehbe, H., Henson, R., Lang, M., Meng, F., Patel, T. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  15. Assignment of the human gene encoding eukaryotic initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4. Jones, R.M., MacDonald, M.E., Branda, J., Altherr, M.R., Louis, D.N., Schmidt, E.V. Somat. Cell Mol. Genet. (1997) [Pubmed]
  16. The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Chiu, S.Y., Lejeune, F., Ranganathan, A.C., Maquat, L.E. Genes Dev. (2004) [Pubmed]
  17. Suppression of cap-dependent translation in mitosis. Pyronnet, S., Dostie, J., Sonenberg, N. Genes Dev. (2001) [Pubmed]
  18. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. Pyronnet, S., Imataka, H., Gingras, A.C., Fukunaga, R., Hunter, T., Sonenberg, N. EMBO J. (1999) [Pubmed]
  19. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. Haghighat, A., Mader, S., Pause, A., Sonenberg, N. EMBO J. (1995) [Pubmed]
  20. Emx2 homeodomain transcription factor interacts with eukaryotic translation initiation factor 4E (eIF4E) in the axons of olfactory sensory neurons. Nédélec, S., Foucher, I., Brunet, I., Bouillot, C., Prochiantz, A., Trembleau, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Differential phosphorylation controls Maskin association with eukaryotic translation initiation factor 4E and localization on the mitotic apparatus. Barnard, D.C., Cao, Q., Richter, J.D. Mol. Cell. Biol. (2005) [Pubmed]
  22. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. Chung, J., Bachelder, R.E., Lipscomb, E.A., Shaw, L.M., Mercurio, A.M. J. Cell Biol. (2002) [Pubmed]
  23. Gamma interferon and cadmium treatments modulate eukaryotic initiation factor 4E-dependent mRNA transport of cyclin D1 in a PML-dependent manner. Topisirovic, I., Capili, A.D., Borden, K.L. Mol. Cell. Biol. (2002) [Pubmed]
  24. Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1. Connor, J.H., Lyles, D.S. J. Virol. (2002) [Pubmed]
  25. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Wang, X., Yue, P., Chan, C.B., Ye, K., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Fu, H., Khuri, F.R., Sun, S.Y. Mol. Cell. Biol. (2007) [Pubmed]
  26. PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA. Cohen, N., Sharma, M., Kentsis, A., Perez, J.M., Strudwick, S., Borden, K.L. EMBO J. (2001) [Pubmed]
  27. Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism. Greenberg, V.L., Zimmer, S.G. Oncogene (2005) [Pubmed]
  28. 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. Miura, T., Shiratori, Y., Shimma, N. J. Biomol. NMR (2003) [Pubmed]
  29. 4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family. Poulin, F., Gingras, A.C., Olsen, H., Chevalier, S., Sonenberg, N. J. Biol. Chem. (1998) [Pubmed]
  30. Protein kinase C-related kinase 2 phosphorylates the protein synthesis initiation factor eIF4E in starfish oocytes. Lee, S.J., Stapleton, G., Greene, J.H., Hille, M.B. Dev. Biol. (2000) [Pubmed]
  31. Casein kinase I phosphorylates the 25-kDa mRNA cap-binding protein. Haas, D.W., Hagedorn, C.H. Arch. Biochem. Biophys. (1991) [Pubmed]
  32. The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth. Topisirovic, I., Culjkovic, B., Cohen, N., Perez, J.M., Skrabanek, L., Borden, K.L. EMBO J. (2003) [Pubmed]
  33. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Knauf, U., Tschopp, C., Gram, H. Mol. Cell. Biol. (2001) [Pubmed]
  34. Features in the N and C termini of the MAPK-interacting kinase Mnk1 mediate its nucleocytoplasmic shuttling. Parra-Palau, J.L., Scheper, G.C., Wilson, M.L., Proud, C.G. J. Biol. Chem. (2003) [Pubmed]
  35. Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma. Wang, S., Lloyd, R.V., Hutzler, M.J., Rosenwald, I.B., Safran, M.S., Patwardhan, N.A., Khan, A. Thyroid (2001) [Pubmed]
  36. Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels. Topisirovic, I., Kentsis, A., Perez, J.M., Guzman, M.L., Jordan, C.T., Borden, K.L. Mol. Cell. Biol. (2005) [Pubmed]
  37. Regulation of translation initiation factor gene expression during human T cell activation. Mao, X., Green, J.M., Safer, B., Lindsten, T., Frederickson, R.M., Miyamoto, S., Sonenberg, N., Thompson, C.B. J. Biol. Chem. (1992) [Pubmed]
  38. Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20. Pelletier, J., Brook, J.D., Housman, D.E. Genomics (1991) [Pubmed]
  39. Eukaryotic initiation factor 4E (eIF4E) and angiogenesis: prognostic markers for breast cancer. Zhou, S., Wang, G.P., Liu, C., Zhou, M. BMC Cancer (2006) [Pubmed]
  40. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Marcotrigiano, J., Gingras, A.C., Sonenberg, N., Burley, S.K. Mol. Cell (1999) [Pubmed]
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