eukaryotic initiation factor 4f


Summary: A trimeric peptide initiation factor complex that associates with the 5' MRNA cap structure of RNA (RNA CAPS) and plays an essential role in MRNA TRANSLATION. It is composed of EUKARYOTIC INITIATION FACTOR-4A; EUKARYOTIC INITIATION FACTOR-4E; and EUKARYOTIC INITIATION FACTOR-4G.

Top Publications

  1. Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman D, et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 2004;5:553-63 pubmed
    ..Thus, eIF4F activation is an essential component of the malignant phenotype in breast carcinoma. ..
  2. Caron S, Charon M, Cramer E, Sonenberg N, Dusanter Fourt I. Selective modification of eukaryotic initiation factor 4F (eIF4F) at the onset of cell differentiation: recruitment of eIF4GII and long-lasting phosphorylation of eIF4E. Mol Cell Biol. 2004;24:4920-8 pubmed
    ..Our data further indicate that cytokines such as thrombopoietin can differentially regulate eIF4GI/II activities. These results provide the first evidence that eIF4GI/II does fulfill selective roles in mammalian cells. ..
  3. Mader S, Lee H, Pause A, Sonenberg N. 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. Mol Cell Biol. 1995;15:4990-7 pubmed
    ..These results shed light on the mechanisms of eIF-4F assembly and on the translational regulation by insulin and growth factors. ..
  4. Goyer C, Altmann M, Lee H, Blanc A, Deshmukh M, Woolford J, et al. TIF4631 and TIF4632: two yeast genes encoding the high-molecular-weight subunits of the cap-binding protein complex (eukaryotic initiation factor 4F) contain an RNA recognition motif-like sequence and carry out an essential function. Mol Cell Biol. 1993;13:4860-74 pubmed
    ..Sequence comparison of TIF4631, TIF4632, and the human eIF-4F p220 subunit revealed significant stretches of homology. We have thus cloned two yeast homologs of mammalian p220. ..
  5. Gradi A, Imataka H, Svitkin Y, Rom E, Raught B, Morino S, et al. A novel functional human eukaryotic translation initiation factor 4G. Mol Cell Biol. 1998;18:334-42 pubmed
    ..These results may have important implications for the understanding of the mechanism of shutoff of host protein synthesis following picornavirus infection. ..
  6. Marcotrigiano J, Gingras A, Sonenberg N, Burley S. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell. 1999;3:707-16 pubmed
    ..The implications of our results for translation initiation are discussed in detail, and a molecular mechanism for relief of translation inhibition following phosphorylation of the 4E-BPs is proposed. ..
  7. Hundsdoerfer P, Thoma C, Hentze M. Eukaryotic translation initiation factor 4GI and p97 promote cellular internal ribosome entry sequence-driven translation. Proc Natl Acad Sci U S A. 2005;102:13421-6 pubmed
  8. Vary T, Deiter G, Lynch C. Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr. 2007;137:1857-62 pubmed
    ..Furthermore, the rapamycin-sensitive reductions in phosphorylation of eIF4G may also lead to decreased formation of active eIF4G-eIF4E complex. ..
  9. Dhalia R, Reis C, Freire E, Rocha P, Katz R, Muniz J, et al. Translation initiation in Leishmania major: characterisation of multiple eIF4F subunit homologues. Mol Biochem Parasitol. 2005;140:23-41 pubmed
    ..Therefore for each factor, one of the L. major forms seems to fulfil, in part at least, the expected characteristics of a translational initiation factor. ..

Scientific Experts

More Information


  1. Rogers G, Richter N, Lima W, Merrick W. Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. J Biol Chem. 2001;276:30914-22 pubmed
    ..A simple model of how eIF4B or eIF4H affects the duplex unwinding mechanism of eIF4A is proposed. ..
  2. Huang B, Wang Y, Wang X, Wang Z, Proud C. Blocking eukaryotic initiation factor 4F complex formation does not inhibit the mTORC1-dependent activation of protein synthesis in cardiomyocytes. Am J Physiol Heart Circ Physiol. 2009;296:H505-14 pubmed publisher
    ..Therefore, other mTORC1 targets are more important in the inhibition by rapamycin of the rapid activation of protein synthesis and of cell growth. ..
  3. Gingras A, Raught B, Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem. 1999;68:913-63 pubmed
    ..The recent determination of the structure of eIF4E at atomic resolution has provided insight about how translation is initiated and regulated. Evidence suggests that eIF4F is also implicated in malignancy and apoptosis. ..
  4. Herbert T, Kilhams G, Batty I, Proud C. Distinct signalling pathways mediate insulin and phorbol ester-stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells. J Biol Chem. 2000;275:11249-56 pubmed
    ..This report also provides evidence that increased eIF4E phosphorylation alone does not affect the assembly of the eIF4F complex or general protein synthesis. ..
  5. Shen W, Boyle D, Wisniowski P, Bade A, Liechty E. Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids. J Endocrinol. 2005;185:275-89 pubmed
    ..We conclude that in C2C12 myotubes, insulin and IGF-I may regulate protein synthesis and translation initiation independent of external amino acid supply via the phosphatidylinositol-3 kinase-PKB/Akt-mTOR pathway. ..
  6. Tarun S, Wells S, Deardorff J, Sachs A. Translation initiation factor eIF4G mediates in vitro poly(A) tail-dependent translation. Proc Natl Acad Sci U S A. 1997;94:9046-51 pubmed
    ..These data suggest that eIF4G mediates poly(A) tail stimulated translation in vitro, and that Pab1p and the domain encompassing the Pab1p-binding site on eIF4G can compensate for partial loss of eIF4E function in vivo. ..
  7. Kaye N, Emmett K, Merrick W, Jankowsky E. Intrinsic RNA binding by the eukaryotic initiation factor 4F depends on a minimal RNA length but not on the m7G cap. J Biol Chem. 2009;284:17742-50 pubmed publisher
    The eukaryotic initiation factor 4F (eIF4F) is thought to be the first factor to bind mRNA during 7-methylguanosine (m7G) cap-dependent translation initiation...
  8. O Loghlen A, PĂ©rez Morgado M, Salinas M, Martin M. N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways. Cell Signal. 2006;18:21-31 pubmed
    ..Altogether our findings suggest that the effects caused by oxidative stress on eIF4s factors depends on two MAP kinase-independent signal transduction pathways, being at least one of them rapamycin-dependent. ..
  9. Mir M, Panganiban A. A protein that replaces the entire cellular eIF4F complex. EMBO J. 2008;27:3129-39 pubmed publisher
    ..The ability of N to directly mediate translation initiation would ensure the efficient translation of viral mRNA. ..
  10. Majumdar R, Maitra U. Regulation of GTP hydrolysis prior to ribosomal AUG selection during eukaryotic translation initiation. EMBO J. 2005;24:3737-46 pubmed
    ..These results, taken together, demonstrate the biochemical requirements for regulation of GTP hydrolysis and its coupling to the AUG selection process during translation initiation. ..
  11. Dorrello N, Peschiaroli A, Guardavaccaro D, Colburn N, Sherman N, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314:467-71 pubmed
    ..We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth. ..
  12. Chuluunbaatar U, Roller R, Feldman M, Brown S, Shokat K, Mohr I. Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication. Genes Dev. 2010;24:2627-39 pubmed publisher
    ..Thus, HSV-1 encodes an Akt surrogate with overlapping substrate specificity to activate mTORC1, stimulating translation and virus replication. This establishes Us3 as a unique viral kinase with promising drug development potential...
  13. Sonenberg N, Pause A. Signal transduction. Protein synthesis and oncogenesis meet again. Science. 2006;314:428-9 pubmed
  14. Willett M, Flint S, Morley S, Pain V. Compartmentalisation and localisation of the translation initiation factor (eIF) 4F complex in normally growing fibroblasts. Exp Cell Res. 2006;312:2942-53 pubmed
  15. Mauro V, Edelman G, Zhou W. Reevaluation of the conclusion that IRES-activity reported within the 5' leader of the TIF4631 gene is due to promoter activity. RNA. 2004;10:895-7; discussion 898 pubmed
    ..We disagree with these conclusions and respond by showing that the data are most consistent with an internal initiation mechanism. ..
  16. Proud C. The eukaryotic initiation factor 4E-binding proteins and apoptosis. Cell Death Differ. 2005;12:541-6 pubmed
  17. Cowan J, Morley S. The proteasome inhibitor, MG132, promotes the reprogramming of translation in C2C12 myoblasts and facilitates the association of hsp25 with the eIF4F complex. Eur J Biochem. 2004;271:3596-611 pubmed
  18. Luo Y, Goss D. Homeostasis in mRNA initiation: wheat germ poly(A)-binding protein lowers the activation energy barrier to initiation complex formation. J Biol Chem. 2001;276:43083-6 pubmed
    ..The reduced energy barrier for formation of a cap.eIFiso4F complex suggests a more stable platform for further initiation complex formation and a possible means of adapting to varying temperature conditions. ..
  19. Stover P. New paradigms for nutrient control of genome translation. Nutr Rev. 2003;61:427-31 pubmed
  20. Constantinou C, Bushell M, Jeffrey I, Tilleray V, West M, Frost V, et al. p53-induced inhibition of protein synthesis is independent of apoptosis. Eur J Biochem. 2003;270:3122-32 pubmed
    ..We conclude that the p53-regulated cleavages of eIF4GI and eIF4B, as well as the overall inhibition of protein synthesis, are caspase-independent events that can be dissociated from the induction of apoptosis per se. ..
  21. Shen W, Mallon D, Boyle D, Liechty E. IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus. Am J Physiol Endocrinol Metab. 2002;283:E593-603 pubmed
    ..Insulin regulates translation initiation via the PI 3-kinase-p70(S6k) pathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70(S6k) pathway. ..
  22. Tee A, Proud C. Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol. 2002;22:1674-83 pubmed
    ..This suggests that the N-terminal sequence of 4E-BP1 is required for optimal regulation of 4E-BPs by insulin. ..
  23. Zaborowska I, Walsh D. PI3K signaling regulates rapamycin-insensitive translation initiation complex formation in vaccinia virus-infected cells. J Virol. 2009;83:3988-92 pubmed publisher
    ..PI3K signaling, therefore, plays a critical role in regulating protein production during VV infection, at least in part by controlling the abundance and activity of 4E-BP1. ..
  24. Allen M, Metz A, Timmer R, Rhoads R, Browning K. Isolation and sequence of the cDNAs encoding the subunits of the isozyme form of wheat protein synthesis initiation factor 4F. J Biol Chem. 1992;267:23232-6 pubmed
    ..sequences of the cDNAs for the two subunits, p82 and p28, of the isozyme form of wheat germ eukaryotic initiation factor 4F (eIF-(iso)4F) were determined. The cDNA for the p82 subunit encodes a polypeptide of 86,514 Da...
  25. Banko J, Poulin F, Hou L, DeMaria C, Sonenberg N, Klann E. The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci. 2005;25:9581-90 pubmed
    ..These results suggest a crucial role for proper regulation of the eIF4F complex by 4E-BP2 during LTP and learning and memory in the mouse hippocampus. ..
  26. Vary T, Lynch C. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab. 2006;290:E631-42 pubmed
    ..eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E. ..
  27. Costello J, Kershaw C, Castelli L, Talavera D, Rowe W, Sims P, et al. Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses. Genome Biol. 2017;18:201 pubmed publisher
    ..Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions. ..
  28. Walsh D, Arias C, Perez C, Halladin D, Escandon M, Ueda T, et al. Eukaryotic translation initiation factor 4F architectural alterations accompany translation initiation factor redistribution in poxvirus-infected cells. Mol Cell Biol. 2008;28:2648-58 pubmed publisher
    ..Furthermore, it suggests that the subcellular distribution of eIF4F components may potentiate the complex assembly. ..
  29. Lin C, Cencic R, Mills J, Robert F, Pelletier J. c-Myc and eIF4F are components of a feedforward loop that links transcription and translation. Cancer Res. 2008;68:5326-34 pubmed publisher
    The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (eIF4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation...
  30. Svitkin Y, Evdokimova V, Brasey A, Pestova T, Fantus D, Yanagiya A, et al. General RNA-binding proteins have a function in poly(A)-binding protein-dependent translation. EMBO J. 2009;28:58-68 pubmed publisher
    ..Conversely, adding nonspecific RNA abrogated PABP stimulation of eIF4E binding. These data strongly suggest that competition between YB-1 and eIF4G for mRNA binding is required for efficient stimulation of eIF4F activity by PABP. ..
  31. Melemedjian O, Asiedu M, Tillu D, Peebles K, Yan J, Ertz N, et al. IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. J Neurosci. 2010;30:15113-23 pubmed publisher
    ..These results establish IL-6- and NGF-mediated cap-dependent translation of local proteins as a new model for nociceptive plasticity. ..
  32. Piccone M, Rieder E, Mason P, Grubman M. The foot-and-mouth disease virus leader proteinase gene is not required for viral replication. J Virol. 1995;69:5376-82 pubmed
    ..removal from the N terminus of the viral polyprotein and (ii) cleavage of the p220 subunit of the eukaryotic initiation factor 4F complex, which helps to shut off host protein synthesis...
  33. Shaughnessy J, Jenkins N, Copeland N. cDNA cloning, expression analysis, and chromosomal localization of a gene with high homology to wheat eIF-(iso)4F and mammalian eIF-4G. Genomics. 1997;39:192-7 pubmed
    ..Southern blot analysis of DNA from interspecific backcross mice shows that Eif4g2 is localized to distal mouse chromosome 7 in a region syntenic with human chromosome 11p15. ..
  34. Jackson R, Wickens M. Translational controls impinging on the 5'-untranslated region and initiation factor proteins. Curr Opin Genet Dev. 1997;7:233-41 pubmed
    ..Initiation is regulated by the MAP kinase and rapamycin-sensitive signalling pathways, which control phosphorylation of elF4E and 4E-BP1, a protein which in the dephosphorylated form binds and sequesters elF4E. ..
  35. Pisarev A, Skabkin M, Thomas A, Merrick W, Ovchinnikov L, Shatsky I. Positive and negative effects of the major mammalian messenger ribonucleoprotein p50 on binding of 40 S ribosomal subunits to the initiation codon of beta-globin mRNA. J Biol Chem. 2002;277:15445-51 pubmed
    ..These data are best compatible with the functional role of p50 as a "manager" of mRNA-protein interactions in mammalian mRNPs. ..
  36. Sans M, DiMagno M, D Alecy L, Williams J. Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F. Am J Physiol Gastrointest Liver Physiol. 2003;285:G517-28 pubmed
  37. Kaufman R, Murtha Riel P, Pittman D, Davies M. Characterization of wild-type and Ser53 mutant eukaryotic initiation factor 4E overexpression in mammalian cells. J Biol Chem. 1993;268:11902-9 pubmed
    ..These results demonstrate that phosphorylation of eIF-4E at residue 53 is not required for interaction with p220 and suggest that Ser53 phosphorylation may not be required for cap-dependent translation initiation in this system. ..
  38. Yueh A, Schneider R. Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA. Genes Dev. 2000;14:414-21 pubmed
    ..The importance of mRNA complementarity to 18S rRNA suggests that ribosome shunting may involve either specific RNA structural features or a prokaryotic-like interaction between mRNA and rRNA. ..
  39. Cuesta R, Laroia G, Schneider R. Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation of cap-initiation complexes. Genes Dev. 2000;14:1460-70 pubmed
    ..These results therefore demonstrate that Hsp27 is a heat-induced inhibitor of eIF4F-dependent mRNA translation. ..
  40. Mathonnet G, Fabian M, Svitkin Y, Parsyan A, Huck L, Murata T, et al. MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science. 2007;317:1764-7 pubmed
    ..Our results indicate that inhibition of translation initiation is the earliest molecular event effected by miRNAs. Other mechanisms, such as mRNA degradation, may subsequently consolidate mRNA silencing...
  41. Borman A, Michel Y, Kean K. Detailed analysis of the requirements of hepatitis A virus internal ribosome entry segment for the eukaryotic initiation factor complex eIF4F. J Virol. 2001;75:7864-71 pubmed
  42. Freire M. Translation initiation factor (iso) 4E interacts with BTF3, the beta subunit of the nascent polypeptide-associated complex. Gene. 2005;345:271-7 pubmed
    ..These findings provide a molecular link between the translation initiation mechanism and the emergence of the nascent polypeptide chains. ..
  43. Vilela C, Velasco C, Ptushkina M, McCarthy J. The eukaryotic mRNA decapping protein Dcp1 interacts physically and functionally with the eIF4F translation initiation complex. EMBO J. 2000;19:4372-82 pubmed
    ..These data on interactions at the interface between translation and mRNA decay suggest how events at the 5' cap and 3' poly(A) tail might be coupled. ..
  44. Cencic R, Yan Y, Pelletier J. Homogenous time resolved fluorescence assay to identify modulators of cap-dependent translation initiation. Comb Chem High Throughput Screen. 2007;10:181-8 pubmed
    ..We have performed a small molecule chemical screen of >73,000 compounds using this assay. ..
  45. Kimball S. Regulation of global and specific mRNA translation by amino acids. J Nutr. 2002;132:883-6 pubmed
    ..Thus, deprivation of essential amino acids not only directly and rapidly represses global mRNA translation, but also potentially results in a reduction in the capacity to synthesize protein. ..
  46. Saliner A, Netzeva T, Worth A. Prediction of estrogenicity: validation of a classification model. SAR QSAR Environ Res. 2006;17:195-223 pubmed
    ..In addition, the model was shown to meet the OECD Principles for (Q)SAR Validation, making it potentially useful for regulatory purposes. ..
  47. Vary T, Lang C. IGF-I activates the eIF4F system in cardiac muscle in vivo. Mol Cell Biochem. 2005;272:209-20 pubmed
    ..Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway. ..
  48. Pyronnet S, Dostie J, Sonenberg N. Suppression of cap-dependent translation in mitosis. Genes Dev. 2001;15:2083-93 pubmed
    ..Thus, inhibition of cap-dependent translation in mitosis results from a combination of phosphorylation modifications leading to eIF4F complex disruption. ..
  49. Kimball S, Jefferson L, Nguyen H, Suryawan A, Bush J, Davis T. Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR-dependent process. Am J Physiol Endocrinol Metab. 2000;279:E1080-7 pubmed
    ..However, in skeletal muscle, these two processes may account for only part of the stimulation of protein synthesis, and thus additional steps may be involved in the response...
  50. Jefferson L, Kimball S. Amino acid regulation of gene expression. J Nutr. 2001;131:2460S-6S; discussion 2486S-7S pubmed publisher
    ..It concludes with a consideration of some of the important unanswered questions in this rapidly advancing area of research. ..
  51. Lellis A, Kasschau K, Whitham S, Carrington J. Loss-of-susceptibility mutants of Arabidopsis thaliana reveal an essential role for eIF(iso)4E during potyvirus infection. Curr Biol. 2002;12:1046-51 pubmed
    ..eIF4E and eIF(iso)4E from different plant species were shown previously to interact with the genome-linked protein (VPg) of TEV and TuMV, respectively. Models to explain the roles of eIF(iso)4E during virus infection are presented. ..
  52. Murooka T, Rahbar R, Fish E. CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation. Biochem Biophys Res Commun. 2009;387:381-6 pubmed publisher
    ..Taken together, we describe a mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs, thereby providing CCR5-positive breast cancer cells with a proliferative advantage. ..
  53. Ling J, Morley S, Pain V, Marzluff W, Gallie D. The histone 3'-terminal stem-loop-binding protein enhances translation through a functional and physical interaction with eukaryotic initiation factor 4G (eIF4G) and eIF3. Mol Cell Biol. 2002;22:7853-67 pubmed
    ..These data indicate that SLBP stimulates the translation of histone mRNAs through a functional interaction with both the mRNA stem-loop and the 5' cap that is mediated by eIF4G and eIF3. ..