Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4A1
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,572,825-7,579,006 (from NCBI)
The eukaryotic initiation factor-4A family consists of 2 closely related genes, EIF4A1 and EIF4A2 (601102). These factors are required for the binding of mRNA to 40S ribosomal subunits. Nielsen et al. (1985) cloned eif4a1 cDNAs from mouse liver. They identified 2 distinct cDNAs differing in their untranslated regions. The sizes of these cDNAs correspond to 2 discrete mRNA bands of 2.0 and 1.6 kb seen on Northern blots of both mouse and human cells. Nielsen and Trachsel (1988) found that eif4a1 was expressed at similar levels in all mouse tissues examined, while eif4a2 had a much more varied pattern of expression.
Kim et al. (1993) cloned the human EIF4A1 cDNA. The EIF4A1 cDNA encodes a predicted 406-amino acid polypeptide with 92.7% amino acid similarity to the mouse protein. Kukimoto et al. (1997) characterized the promoter region of human EIF4A1. The minimal promoter contains TATA and CAAT motifs and consensus sequences for binding to SP1 and AP2.
By fluorescence in situ hybridization, Jones et al. (1998) mapped the linked EIF4A1 and CD68 (153634) genes to 17p13. By interspecific backcross analysis, they mapped the mouse Eif4a1 and Cd68 genes to chromosome 11.
Cruz-Migoni et al. (2011) found that BPSL1549, a Burkholderia pseudomallei toxin, promotes deamidation of glu339 of the translation initiation factor Eif4a, abolishing its helicase activity and inhibiting translation.
Wolfe et al. (2014) reported an EIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, EIF4A promotes T-cell acute lymphoblastic leukemia development in vivo and is required for leukemia maintenance. Accordingly, inhibition of EIF4A with silvestrol has powerful therapeutic effects against murine and human leukemic cells in vitro and in vivo. Wolfe et al. (2014) used transcriptome-scale ribosome footprinting to identify the hallmarks of EIF4A-dependent transcripts. These include 5-prime untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most EIF4A-dependent and silvestrol-sensitive transcripts were a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Wolfe et al. (2014) concluded that the 5-prime UTRs of select cancer genes harbor a targetable requirement for the EIF4A RNA helicase.
Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK (176872), and anti-BRAF plus anti-MEK drug combinations in BRAF(V600) (164757.0001)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.
Using a single-molecule assay, Garcia-Garcia et al. (2015) found that eiF4A functions as an ATP-dependent processive helicase when complexed with 2 accessory proteins, eIF4G and eIf4B (603928). Translocation occurred in discrete steps of 11 +/- 2 basepairs, irrespective of the accessory factor combination. Garcia-Garcia et al. (2015) concluded that their findings supported a memoryless stepwise mechanism for translation initiation and suggested that similar factor-dependent processivity may be shared by other members of the DEAD-box helicase family.
Boussemart, L., Malka-Mahieu, H., Girault, I., Allard, D., Hemmingsson, O., Tomasic, G., Thomas, M., Basmadjian, C., Ribeiro, N., Thuaud, F., Mateus, C., Routier, E., Kamsu-Kom, N., Agoussi, S., Eggermont, A. M., Desaubry, L., Robert, C., Vagner, S. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 513: 105-109, 2014. [PubMed: 25079330] [Full Text: https://doi.org/10.1038/nature13572]
Cruz-Migoni, A., Hautbergue, G. M., Artymiuk, P. J., Baker, P. J., Bokori-Brown, M., Chang, C.-T., Dickman, M. J., Essex-Lopresti, A., Harding, S. V., Mahadi, N. M., Marshall, L. E., Mobbs, G. W., and 16 others. A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor elF4A. Science 334: 821-824, 2011. [PubMed: 22076380] [Full Text: https://doi.org/10.1126/science.1211915]
Garcia-Garcia, C., Frieda, K. L., Feoktistova, K., Fraser, C. S., Block, S. M. Factor-dependent processivity in human eIF4A DEAD-box helicase. Science 348: 1486-1488, 2015. [PubMed: 26113725] [Full Text: https://doi.org/10.1126/science.aaa5089]
Jones, E., Quinn, C. M., See, C. G., Montgomery, D. S., Ford, M. J., Kolble, K., Gordon, S., Greaves, D. R. The linked human elongation initiation factor 4A1 (EIF4A1) and CD68 genes map to chromosome 17p13. Genomics 53: 248-250, 1998. [PubMed: 9790779] [Full Text: https://doi.org/10.1006/geno.1998.5515]
Kim, N.-S., Kato, T., Abe, N., Kato, S. Nucleotide sequence of human cDNA encoding eukaryotic initiation factor 4A1. Nucleic Acids Res. 21: 2012 only, 1993. [PubMed: 8493113] [Full Text: https://doi.org/10.1093/nar/21.8.2012]
Kukimoto, I., Watanabe, S., Taniguchi, K., Ogata, T., Yoshiike, K., Kanda, T. Characterization of the cloned promoter of the human initiation factor 4A1 gene. Biochem. Biophys. Res. Commun. 233: 844-847, 1997. [PubMed: 9168945] [Full Text: https://doi.org/10.1006/bbrc.1997.6555]
Nielsen, P. J., McMaster, G. K., Trachsel, H. Cloning of eukaryotic protein synthesis initiation factor genes: isolation and characterization of cDNA clones encoding factor eIF-4A. Nucleic Acids Res. 13: 6867-6880, 1985. [PubMed: 3840589] [Full Text: https://doi.org/10.1093/nar/13.19.6867]
Nielsen, P. J., Trachsel, H. The mouse protein synthesis initiation factor 4A gene family includes two related functional genes which are differentially expressed. EMBO J. 7: 2097-2105, 1988. [PubMed: 3046931] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03049.x]
Wolfe, A. L., Singh, K., Zhong, Y., Drewe, P., Rajasekhar, V. K., Sanghvi, V. R., Mavrakis, K. J., Jiang, M., Roderick, J. E., Van der Meulen, J., Schatz, J. H., Rodrigo, C. M., and 10 others. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513: 65-70, 2014. [PubMed: 25079319] [Full Text: https://doi.org/10.1038/nature13485]