Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4EBP1
Cytogenetic location: 8p11.23 Genomic coordinates (GRCh38): 8:38,030,534-38,060,365 (from NCBI)
Pause et al. (1994) used interaction cloning to identify 2 novel proteins that interacted with eIF4E (133440), and termed these binding proteins 4EBP1 and 4EBP2 (602224). Pause et al. (1994) reported that the 4EBP1 gene encodes a 118-amino acid polypeptide that is 56% identical to that of 4EBP2.
Rat PHAS-I was isolated as a protein phosphorylated in response to insulin in rat adipose tissue. PHAS-I is phosphorylated in response to growth factors and phorbol esters. Pause et al. (1994) noted that the 4EBP1 amino acid sequence was 93% identical to the rat protein PHAS-I, thus representing the human homolog.
Pause et al. (1994) showed that insulin treatment of adipose cells increased the phosphorylation of 4EBP1 and reduced the interaction of 4EBP1 with eIF4E. The authors speculated that the dissociation of the eIF4E binding proteins may be responsible for the enhanced translational activity in adipose tissue upon insulin treatment. Rousseau et al. (1996) showed that 4EBP1 and 4EBP2 are negative regulators of cell growth. They found that overexpression of either 4EBP1 or 4EBP2 could partially reverse the phenotype of cells transformed by v-src (see 190090) or Ha-v-ras (see 190020). By Northern blot analysis, Tsukiyama-Kohara et al. (1996) showed that 4EBP1 is expressed in most tissues, with highest levels seen in adipose tissue, pancreas, and skeletal muscle. The authors noted that 4EBP1 is more strongly phosphorylated in response to insulin treatment than is 4EBP2, suggesting that 4EBP1 may be more significantly involved in insulin-mediated control pathways.
In mammals, MTOR (601231) cooperates with PI3K (see 171834)-dependent effectors in a biochemical signaling pathway to regulate the size of proliferating cells. Fingar et al. (2002) presented evidence that rat S6k1 alpha-II (608938), Eif4e, and Eif4ebp1 mediate Mtor-dependent cell size control.
Colina et al. (2008) showed that translational control is critical for induction of type I interferon (see 147570) production. In mouse embryonic fibroblasts lacking the translational repressors 4Ebp1 and 4Ebp2, the threshold for eliciting type I interferon production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus, and Sindbis virus is markedly suppressed. Furthermore, Colina et al. (2008) showed that mice with both 4Ebp1 and 4Ebp2 genes knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type I interferon production in plasmacytoid dendritic cells and the expression of interferon-regulated genes in the lungs. The enhanced type I interferon response of 4Ebp1 -/- 4Ebp2 -/- double knockout mouse embryonic fibroblasts is caused by upregulation of interferon regulatory factor-7 (Irf7; 605047) mRNA translation. Colina et al. (2008) found that their findings highlighted the role of 4EBPs as negative regulators of type I interferon production, via translational repression of IRF7 mRNA.
Dowling et al. (2010) inhibited the mTORC1 (601231) pathway in cells lacking EIF4EBP1, EIF4EBP2 (602224), and EIF4EBP3 (603483) and analyzed the effects on cell size, cell proliferation, and cell cycle progression. Although the EIF4EBPs had no effect on cell size, they inhibited cell proliferation by selectively inhibiting the translation of mRNAs that encode proliferation-promoting proteins and proteins involved in cell cycle progression. Thus, Dowling et al. (2010) concluded that control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, EIF4E binding proteins influence both cell growth and proliferation.
Demontis and Perrimon (2010) showed that signaling through the transcription factor Foxo (see 136533) and its target Thor/4Ebp regulated aging in Drosophila muscle. Increased activity of Foxo and 4Ebp delayed age-related muscle weakness and preserved muscle function, at least in part, by promoting basal activity of the autophagy/lysosome system for the elimination of deleterious protein aggregates. Foxo/4Ebp signaling in muscle also decreased feeding behavior and the release of insulin, which in turn delayed age-related accumulation of protein aggregates in other tissues, increasing life span.
Thoreen et al. (2012) used high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin-1, which, unlike rapamycin, fully inhibits mTORC1. Their data revealed a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. mTORC1 phosphorylates a myriad of translational regulators, but how it controls 5-prime terminal oligopyrimidine (TOP) mRNA translation was unknown. Remarkably, loss of just the 4EBP family of translational repressors, arguably the best characterized mTORC1 substrates, was sufficient to render TOP and TOP-like mRNA translation resistant to Torin-1. The 4EBPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E (133440) and eIF4G1 (600495). Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation.
Tsukiyama-Kohara et al. (1996) analyzed the genomic structure of the mouse EIF4EBP1 gene and showed that it consists of 3 exons and spans 16 kb. The authors also noted that EIF4EBP1 has at least 2 pseudogenes in the mouse genome.
Tsukiyama-Kohara et al. (1996) used fluorescence in situ hybridization to map the 4EBP1 gene to human chromosome 8p12 and to mouse chromosome 8A4-B1. They noted that human tumor suppressor genes in this region have implicated in several human cancers.
Colina, R., Costa-Mattioli, M., Dowling, R. J. O., Jaramillo, M., Tai, L.-H., Breitbach, C. J., Martineau, Y., Larsson, O., Rong, L., Svitkin, Y. V., Makrigiannis, A. P., Bell, J. C., Sonenberg, N. Translational control of the innate immune response through IRF-7. Nature 452: 323-328, 2008. [PubMed: 18272964] [Full Text: https://doi.org/10.1038/nature06730]
Demontis, F., Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143: 813-825, 2010. [PubMed: 21111239] [Full Text: https://doi.org/10.1016/j.cell.2010.10.007]
Dowling, R. J. O., Topisirovic, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., Wang, X., Larsson, O., Selvaraj, A., Liu, Y., Kozma, S. C., Thomas, G., Sonenberg, N. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328: 1172-1176, 2010. [PubMed: 20508131] [Full Text: https://doi.org/10.1126/science.1187532]
Fingar, D. C., Salama, S., Tsou, C., Harlow, E., Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16: 1472-1487, 2002. [PubMed: 12080086] [Full Text: https://doi.org/10.1101/gad.995802]
Pause, A., Belsham, G. J., Gingras, A.-C., Donze, O., Lin, T.-A., Lawrence, J. C., Jr., Sonenberg, N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5-prime-cap function. Nature 371: 762-767, 1994. [PubMed: 7935836] [Full Text: https://doi.org/10.1038/371762a0]
Rousseau, D., Gingras, A.-C., Pause, A., Sonenberg, N. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 13: 2415-2420, 1996. [PubMed: 8957083]
Thoreen, C. C., Chantranupong, L., Keys, H. R., Wang, T., Gray, N. S., Sabatini, D. M. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485: 109-113, 2012. [PubMed: 22552098] [Full Text: https://doi.org/10.1038/nature11083]
Tsukiyama-Kohara, K., Vidal, S. M., Gingras, A.-C., Glover, T. W., Hanash, S. M., Heng, H., Sonenberg, N. Tissue distribution, genomic structure, and chromosome mapping of mouse and human eukaryotic initiation factor 4E-binding proteins 1 and 2. Genomics 38: 353-363, 1996. [PubMed: 8975712] [Full Text: https://doi.org/10.1006/geno.1996.0638]