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Gene Review

Eif2s1  -  eukaryotic translation initiation factor 2...

Rattus norvegicus

Synonyms: Eif2a, Eukaryotic translation initiation factor 2 subunit 1, Eukaryotic translation initiation factor 2 subunit alpha, eIF-2-alpha, eIF-2A, ...
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Disease relevance of Eif2s1

  • The fusion protein expressed by the recombinant phage reacts with eIF-2 alpha antiserum except when the serum is preadsorbed with pure eIF-2 [1].
  • We have expressed the rat brain cDNA in Escherichia coli and have demonstrated that the recombinant enzyme is a hemin-sensitive eIF-2 alpha kinase [2].
  • Eukaryotic initiation factor 2 (eIF-2) presented almost basal activity and levels after 30-minute normothermic ischemia, and the amount of phosphorylated eIF-2 alpha in these samples, as well as in sham-control samples, was undetectable [3].
  • Upregulation of iNOS expression and phosphorylation of eIF-2alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closed head trauma model [4].
  • Sterile inflammation or sepsis caused a 50% increase in the proportion of eIF-2 alpha mRNA associated with the polysomes compared with control.(ABSTRACT TRUNCATED AT 250 WORDS)[5]

High impact information on Eif2s1

  • This leads to eIF-2 kinase-catalyzed eIF-2 alpha-subunit phosphorylation and thus to protein synthesis inhibition [6].
  • The eukaryotic initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) isolated from reticulocyte lysate protects the eIF-2 alpha subunit from eIF-2 kinase-catalyzed phosphorylation and promotes protein synthesis in the presence of active eIF-2 kinases [6].
  • The heme-regulated inhibitor is present in an active form and possibly in equal amounts in both heme-deficient and heme-supplemented reticulocyte lysates but cannot phosphorylate eIF-2 alpha subunit because of the presence of p67 [6].
  • TGF-alpha stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2 alpha, two proteins involved in translation regulation [7].
  • The increase in the amount of eIF-2 alpha in the phosphorylated form apparently was not due to an increase in kinase activity, because there was no change in eIF-2 alpha kinase activity in extracts of liver perfused with medium containing histidinol compared to controls [8].

Biological context of Eif2s1

  • These results are consistent with the view that eIF-2 alpha mRNA translation is very efficient compared to other mRNAs in the cell [1].
  • These results suggest that the induction of eIF-2 alpha in the heat-shock response may be important for restoring the cell's ability to initiate protein synthesis [9].
  • Phosphorylated forms of eukaryotic initiation factor 2 alpha (eIF2 alpha) and RNA-dependent protein kinase-like ER eIF2 alpha kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals [10].
  • Taken together, our findings support a role for PP1 in eIF2 alpha phosphorylation and oxidative stress-triggered translation down regulation [11].
  • It is demonstrated that an increase in c-myc function leads to elevated expression of eIF-4E and eIF-2alpha, increases in net protein synthesis and cell proliferation [12].

Anatomical context of Eif2s1

  • The eIF-2 alpha mRNA is found exclusively in polysomes containing 10 or more ribosomes in exponentially growing HeLa cells [1].
  • The translation of hybrid-selected HeLa cell mRNA produces two proteins which are indistinguishable from authentic HeLa eIF-2 alpha and its phosphorylated form when analyzed by electrophoresis in two-dimensional isoelectrofocusing/sodium dodecyl sulfate-polyacrylamide gels and by partial protease digestion [1].
  • After a 30 min recirculation period, protein synthesis rate, initiation factor 2 (eIF-2) and guanine nucleotide exchange factor (GEF) activities, and the level of phosphorylation of the alpha subunit of eIF-2 (eIF-2 alpha) were determined in the neocortex region of the brain from sham-operated controls and ischaemic animals [13].
  • Fasting and refeeding caused alterations in translation initiation in both skeletal muscle and liver that were not associated with any detectable changes in the activity of eIF2B or in the phosphorylation state of eIF2 alpha [14].
  • Reversible inhibition of the protein phosphatase 1 by hydrogen peroxide. Potential regulation of eIF2 alpha phosphorylation in differentiated PC12 cells [11].

Associations of Eif2s1 with chemical compounds

  • However, in islets, no change in eIF-2 alpha phosphorylation was seen under conditions where eIF-2B activity was increased, implying that glucose regulates eIF-2B via an alternative pathway [15].
  • The results demonstrate the novel finding that the inhibition of protein synthesis in vasopressin-treated livers is caused by a reduction in eIF-2B activity due to an increase in phosphorylation of eIF-2 alpha [16].
  • The translation inhibition correlated with an increased phosphorylation of the alpha subunit of eIF2 (eIF2 alpha) (25% vs. 7%, for FCCP-treated and control cells, respectively) and a 1.7-fold increase in the double-stranded RNA-dependent protein kinase activity [17].
  • We show here that treatment of rat GH3 pituitary cells with Brefeldin A leads to an inhibition of protein synthesis at the level of peptide-chain initiation through a mechanism involving the phosphorylation of the alpha-subunit of eukaryotic initiation factor-2 (eIF-2 alpha) [18].
  • Interestingly, NAC pretreatment protected cells from H(2)O(2)-induced PP1 inactivation and, consequently, it abolished increased H(2)O(2)-induced eIF2 alpha phosphorylation and protein synthesis inhibition [11].

Regulatory relationships of Eif2s1


Other interactions of Eif2s1

  • We studied the effect of staurosporine on two well characterised mammalian eIF-2alpha kinases, the heme-regulated translational inhibitor (HRI), and interferon-inducible double-stranded RNA-activated protein kinase (PKR) [20].
  • Additional experiments implicated the PERK/eIF-2 alpha signaling pathway as a contributor to the higher Gadd153 expression and JNK activation, and greater sensitivity of old cells to ER stress [21].

Analytical, diagnostic and therapeutic context of Eif2s1


  1. Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA. Ernst, H., Duncan, R.F., Hershey, J.W. J. Biol. Chem. (1987) [Pubmed]
  2. Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression. Mellor, H., Flowers, K.M., Kimball, S.R., Jefferson, L.S. J. Biol. Chem. (1994) [Pubmed]
  3. The intraischemic and early reperfusion changes of protein synthesis in the rat brain. eIF-2 alpha kinase activity and role of initiation factors eIF-2 alpha and eIF-4E. Burda, J., Martín, M.E., Gottlieb, M., Chavko, M., Marsala, J., Alcázar, A., Pavón, M., Fando, J.L., Salinas, M. J. Cereb. Blood Flow Metab. (1998) [Pubmed]
  4. Upregulation of iNOS expression and phosphorylation of eIF-2alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closed head trauma model. Petrov, T., Underwood, B.D., Braun, B., Alousi, S.S., Rafols, J.A. J. Neurotrauma (2001) [Pubmed]
  5. Regulation of eukaryotic initiation factor-2 expression during sepsis. Vary, T.C., Jurasinski, C.V., Karinch, A.M., Kimball, S.R. Am. J. Physiol. (1994) [Pubmed]
  6. The eukaryotic initiation factor 2-associated 67-kDa polypeptide (p67) plays a critical role in regulation of protein synthesis initiation in animal cells. Ray, M.K., Datta, B., Chakraborty, A., Chattopadhyay, A., Meza-Keuthen, S., Gupta, N.K. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  7. Transforming growth factor-alpha attenuates N-methyl-D-aspartic acid toxicity in cortical cultures by preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. Petegnief, V., Friguls, B., Sanfeliu, C., Suñol, C., Planas, A.M. J. Biol. Chem. (2003) [Pubmed]
  8. Mechanism of inhibition of peptide chain initiation by amino acid deprivation in perfused rat liver. Regulation involving inhibition of eukaryotic initiation factor 2 alpha phosphatase activity. Kimball, S.R., Antonetti, D.A., Brawley, R.M., Jefferson, L.S. J. Biol. Chem. (1991) [Pubmed]
  9. Alpha subunit of eukaryotic translational initiation factor-2 is a heat-shock protein. Colbert, R.A., Hucul, J.A., Scorsone, K.A., Young, D.A. J. Biol. Chem. (1987) [Pubmed]
  10. Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death. Hayashi, T., Saito, A., Okuno, S., Ferrand-Drake, M., Dodd, R.L., Nishi, T., Maier, C.M., Kinouchi, H., Chan, P.H. J. Cereb. Blood Flow Metab. (2003) [Pubmed]
  11. Reversible inhibition of the protein phosphatase 1 by hydrogen peroxide. Potential regulation of eIF2 alpha phosphorylation in differentiated PC12 cells. O'Loghlen, A., Pérez-Morgado, M.I., Salinas, M., Martín, M.E. Arch. Biochem. Biophys. (2003) [Pubmed]
  12. Upregulated expression of the genes encoding translation initiation factors eIF-4E and eIF-2alpha in transformed cells. Rosenwald, I.B. Cancer Lett. (1996) [Pubmed]
  13. Phosphorylation of the alpha subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat. Burda, J., Martín, M.E., García, A., Alcázar, A., Fando, J.L., Salinas, M. Biochem. J. (1994) [Pubmed]
  14. Modulation of translation initiation in rat skeletal muscle and liver in response to food intake. Yoshizawa, F., Kimball, S.R., Jefferson, L.S. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  15. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. Gilligan, M., Welsh, G.I., Flynn, A., Bujalska, I., Diggle, T.A., Denton, R.M., Proud, C.G., Docherty, K. J. Biol. Chem. (1996) [Pubmed]
  16. Mechanism of the inhibition of protein synthesis by vasopressin in rat liver. Kimball, S.R., Jefferson, L.S. J. Biol. Chem. (1990) [Pubmed]
  17. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) induces initiation factor 2 alpha phosphorylation and translation inhibition in PC12 cells. Muñoz, F., Martín, M.E., Salinas, M., Fando, J.L. FEBS Lett. (2001) [Pubmed]
  18. Brefeldin A inhibits protein synthesis through the phosphorylation of the alpha-subunit of eukaryotic initiation factor-2. Mellor, H., Kimball, S.R., Jefferson, L.S. FEBS Lett. (1994) [Pubmed]
  19. Reactive cysteines of the 90-kDa heat shock protein, Hsp90. Nardai, G., Sass, B., Eber, J., Orosz, G., Csermely, P. Arch. Biochem. Biophys. (2000) [Pubmed]
  20. Resistance of initiation factor 2 (eIF-2alpha) kinases to staurosporine: an approach for assaying the kinases in crude extracts. Martín de la Vega, C., García, A., Martín, M.E., Alcázar, A., Marin, O., Quevedo, C., Salinas, M. Cell. Signal. (1999) [Pubmed]
  21. Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase activation sensitizes aged cells to ER stress. Li, J., Holbrook, N.J. Exp. Gerontol. (2004) [Pubmed]
  22. Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2 alpha. DeGracia, D.J., Sullivan, J.M., Neumar, R.W., Alousi, S.S., Hikade, K.R., Pittman, J.E., White, B.C., Rafols, J.A., Krause, G.S. J. Cereb. Blood Flow Metab. (1997) [Pubmed]
  23. Translational initiation factor eIF-2 subcellular levels and phosphorylation status in the developing rat brain. Martín, M.E., Alcázar, A., Fando, J.L., García, A.M., Salinas, M. Neurosci. Lett. (1993) [Pubmed]
  24. Rat fibroblasts transfected with the human 70-kDa heat shock gene exhibit altered translation and eukaryotic initiation factor 2 alpha phosphorylation following heat shock. Chang, G.C., Liu, R., Panniers, R., Li, G.C. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. (1994) [Pubmed]
  25. Molecular cloning and sequencing of the human heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase from bone marrow culture. Omasa, T., Chen, Y.G., Mantalaris, A., Tsai, Y.C., Wu, J.H. DNA Seq. (2002) [Pubmed]
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