Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;5(3):221–239. doi: 10.1111/j.1582-4934.2001.tb00157.x

Translational regulation in cell stress and apoptosis. Roles of the eIF4E binding proteins

MJ Clemens 1,✉
PMCID: PMC6514779  PMID: 12067482

Abstract

Several mechanisms have been identified by which protein synthesis may be regulated during the response of mammalian cells to physiological stresses and conditions that induce apoptotic cell death (reviewed in Clemens et al., Cell Death and Differentiation 7, 603–615, 2000). Recent developments allow us to up‐date this analysis and in this article I concentrate on one particular aspect of this regulation that has not previously been reviewed in depth in relation to apoptosis, viz. the control of the initiation of protein synthesis by eukaryotic initiation factor eIF4E and the eIF4E binding proteins (4E‐BPs). Changes in the state of phosphorylation of the 4E‐BPs and in the extent of their association with eIF4E occur at an early stage in the response of cells to apoptotic inducers. The review discusses the mechanisms by which these events are regulated and the significance of the changes for the control of protein synthesis, cell proliferation and cell survival.

Keywords: apoptosis, 4E‐binding proteins, eIF4E, mTOR, protein kinases, protein synthesis, stress, translational control

References

  • 1. Pestova T.V., Hellen C.U.T., The structure and function of initiation factors in eukaryotic protein synthesis, Cell. Mol. Life Sci., 57: 651–674, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Pestova T.V., Kolupaeva V.G., Lomakin I.B., Pilipenko E.V., Shatsky I.N., Agol V.I., Hellen C.U.T., Molecular mechanisms of translation initiation in eukaryotes, Proc. Natl. Acad. Sci. USA, 98: 7029–7036, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Sonenberg N., Hershey J.W.B., Mathews M.B., (eds.), Translational Control of Gene Expression, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York , 2000. [Google Scholar]
  • 4. Morley S.J., Curtis P.S., Pain V.M., eIF4G: Translation's mystery factor begins to yield its secrets, RNA Publ. RNA Soc., 3: 1085–1104, 1997. [PMC free article] [PubMed] [Google Scholar]
  • 5. Hentze M., eIF4G: A multipurpose ribosome adaptor Science, 275: 500–501, 1997. [DOI] [PubMed] [Google Scholar]
  • 6. Stoneley M., Chappell S.A., Jopling C.L., Dickens M., MacFarlane M., Willis A.E., c‐Myc protein synthesis is initiated from the internal ribosome entry segment during apoptosis, Mol. Cell. Biol., 20: 1162–1169, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Coldwell M.J., Mitchell S.A., Stoneley M., MacFarlane M., Willis A.E., Initiation of Apaf‐1 translation by internal ribosome entry, Oncogene, 19: 899–905, 2000. [DOI] [PubMed] [Google Scholar]
  • 8. Créancier L., Mercier P., Prats A.C., Morello D., c‐myc internal ribosome entry site activity is developmentally controlled and subjected to a strong translational repression in adult transgenic mice, Mol. Cell. Biol., 21: 1833–1840, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Hellen C.U.T., Sarnow P., Internal ribosome entry sites in eukaryotic mRNA molecules, Genes Dev., 15: 1593–1612, 2001. [DOI] [PubMed] [Google Scholar]
  • 10. Clemens M.J., Protein kinases that phosphorylate eIF2 and eIF2B, and their role in eukaryotic cell translational control In: Hershey J.W.B., Mathews M.B., Sonenberg N., eds., Translational control, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1996, pp. 139–172. [Google Scholar]
  • 11. De Haro C., Méndez R., Santoyo J., The eIF‐2α kinases and the control of protein synthesis, FASEB J., 10: 1378–1387, 1996. [DOI] [PubMed] [Google Scholar]
  • 12. Clemens M.J., Initiation factor eIF2α phosphorylation in stress responses and apoptosis In: Rhoads R.E., ed., Signaling pathways for translation: Stress, calcium and rapamycin, Springer, Berlin , 2001, pp. 57–89. [Google Scholar]
  • 13. Lawrence J.C., Abraham R.T., PHAS/4E‐BPs as regulators of mRNA translation and cell proliferaion, Trends Biochem. Sci., 22: 345–349, 1997. [DOI] [PubMed] [Google Scholar]
  • 14. Raught B., Gingras A.C., eIF4E activity is regulated at multiple levels, Int. J. Biochem. Cell Biol., 31: 43–57, 1999. [DOI] [PubMed] [Google Scholar]
  • 15. Gingras A.C., Raught B., Sonenberg N., eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation, Annu. Rev. Biochem., 68: 913–963, 1999. [DOI] [PubMed] [Google Scholar]
  • 16. Joshi B., Cai A.‐L., Keiper B.D., Minich W.B., Mendez R., Beach C.M., Stepinski J., Stolarski R., Darzynkiewicz E., Rhoads R.E., Phosphorylation of eukaryotic protein synthesis initiation factor 4E at Ser‐209, J. Biol. Chem., 270: 14597–14603, 1995. [DOI] [PubMed] [Google Scholar]
  • 17. Frederickson R.M., Mushynski W.E., Sonenberg N., Phosphorylation of translation initiation factor eIF‐4E is induced in a ras‐dependent manner during nerve growth factor‐mediated PC12 cell differentiation, Mol. Cell. Biol., 12: 1239–1247, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Minich W.B., Balasta M.L., Goss D.J., Rhoads R.E., Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF‐4E: Increased cap affinity of the phosphorylated form, Proc. Natl. Acad. Sci. USA, 91: 7668–7672, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Sonenberg N., mRNA 5′ cap‐binding protein eIF4E and control of cell growth In: Hershey J.W.B., Mathews M.B., Sonenberg N., eds., Translational Control, Cold Spring Harbor Laboratory Press, Cold Spring Harbor , 1996, pp. 245–269. [Google Scholar]
  • 20. Knauf U., Tschopp C., Gram H., Negative regulation of protein translation by mitogen‐activated protein kinase‐interacting kinases 1 and 2, Mol. Cell. Biol., 21: 5500–5511, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Tee A.R., Proud C.G., DNA‐damaging agents cause inactivation of translational regulators linked to mTOR signalling, Oncogene, 19: 3021–3031, 2000. [DOI] [PubMed] [Google Scholar]
  • 22. Morley S.J., Jeffrey I., Bushell M., Pain V.M., Clemens M.J., Differential requirements for caspase‐8 activity in the mechanism of phosphorylation of eIF2α, cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells, FEBS Lett., 477: 229–236, 2000. [DOI] [PubMed] [Google Scholar]
  • 23. Clemens M.J., Bushell M., Morley S.J., Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines, Oncogene, 17: 2921–2931, 1998. [DOI] [PubMed] [Google Scholar]
  • 24. Marissen W.E., Lloyd R.E., Eukaryotic translation initiation factor 4G is targeted for proteolytic cleavage by caspase 3 during inhibition of translation in apoptotic cells, Mol. Cell. Biol., 18: 7565–7574, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Bushell M., McKendrick L., Jänicke R.U., Clemens M.J., Morley S.J., Caspase‐3 is necessary and sufficient for cleavage of protein synthesis eukaryotic initiation factor 4G during apoptosis, FEBS Lett., 451: 332–336, 1999. [DOI] [PubMed] [Google Scholar]
  • 26. Satoh S., Hijikata M., Handa H., Shimotohno K., Caspase‐mediated cleavage of eukaryotic translation initiation factor subunit 2α, Biochem. J., 342: 65–70, 1999. [PMC free article] [PubMed] [Google Scholar]
  • 27. Bushell M., Wood W., Clemens M.J., Morley S.J., Changes in integrity and association of eukaryotic protein synthesis initiation factors during apoptosis, Eur. J. Biochem., 267: 1083–1091, 2000. [DOI] [PubMed] [Google Scholar]
  • 28. Marissen W.E., Guo Y.W., Thomas A.A.M., Matts R.L., Lloyd R.E., Identification of caspase 3‐mediated cleavage and functional alteration of eukaryotic initiation factor 2α in apoptosis, J. Biol. Chem., 275: 9314–9323, 2000. [DOI] [PubMed] [Google Scholar]
  • 29. Bushell M., Poncet D., Marissen W.E., Flotow H., Lloyd R.E., Clemens M.J., Morley S.J., Cleavage of polypeptide chain initiation factor eIF4GI during apoptosis: Characterisation of an internal fragment generated by caspase‐3‐mediated cleavage, Cell Death Differ., 7: 628–636, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. Marissen W.E., Gradi A., Sonenberg N., Lloyd R.E., Cleavage of eukaryotic translation initiation factor 4GII correlates with translation inhibition during apoptosis, Cell Death Differ., 7: 1234–1243, 2000. [DOI] [PubMed] [Google Scholar]
  • 31. Clemens M.J, Bushell M., Jeffrey I.W., Pain V.M., Morley S.J., Translation initiation factor modifications and the regulation of protein synthesis in apoptotic cells, Cell Death Differ., 7: 603–615, 2000. [DOI] [PubMed] [Google Scholar]
  • 32. Karim M.M., Hughes J.M.X., Warwicker J., Scheper G.C., Proud C.G., McCarthy J.E.G., A quantitative molecular model for modulation of mammalian translation by the eIF4E‐binding protein 1, J. Biol. Chem., 276: 20750–20757, 2001. [DOI] [PubMed] [Google Scholar]
  • 33. Marcotrigiano J., Gingras A.C., Sonenberg N., Burley S.K., Cap‐dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G, Mol. Cell, 3: 707–716, 1999. [DOI] [PubMed] [Google Scholar]
  • 34. Holcik M., Yeh C., Korneluk R.G., Chow T., Translational upregulation of X‐linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death, Oncogene, 19: 4174–4177, 2000. [DOI] [PubMed] [Google Scholar]
  • 35. Holcik M., Sonenberg N., Korneluk R.G., Internal ribosome initiation of translation and the control of cell death, Trends Genet., 16: 469–473, 2000. [DOI] [PubMed] [Google Scholar]
  • 36. Kleijn M., Proud C.G., Glucose and amino acids modulate translation factor activation by growth factors in PC12 cells, Biochem. J., 347: 399–406, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Lynch C.J., Fox H.L., Vary T.C., Jefferson L.S., Kimball S.R., Regulation of amino acid‐sensitive TOR signaling by leucine analogues in adipocytes, J. Cell. Biochem., 77: 234–251, 2000. [DOI] [PubMed] [Google Scholar]
  • 38. Anthony J.C., Anthony T.G., Kimball S.R., Jefferson L.S., Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine, J. Nutr., 131: 856S–860S, 2001. [DOI] [PubMed] [Google Scholar]
  • 39. Sheikh M.S., Forance A.J., Jr. , Regulation of translation initiation following stress, Oncogene, 18: 6121–6128, 1999. [DOI] [PubMed] [Google Scholar]
  • 40. Yoshizawa F., Kimball S.R., Vary T.C., Jefferson L.S., Effect of dietary protein on translation initiation in rat skeletal muscle and liver, Am. J. Physiol. Endocrinol. Metab., 275: E814–E820, 1998. [DOI] [PubMed] [Google Scholar]
  • 41. Kimball S.R., Horetsky R.L., Jefferson L.S., Implication of eIF2B rather than eIF4E in the regulation of global protein synthesis by amino acids in L6 myoblasts, J. Biol. Chem., 273: 30945–30953, 1998. [DOI] [PubMed] [Google Scholar]
  • 42. Fox H.L., Pham P.T., Kimball S.R., Jefferson L.S., Lynch C.J., Amino acid effects on translational repressor 4E‐BP1 are mediated primarily by L‐leucine in isolated adipocytes, Am. J. Physiol. Cell Physiol., 275: C1232–C1238, 1998. [DOI] [PubMed] [Google Scholar]
  • 43. Kimball S.R., Shantz L.M., Horetsky R.L., Jefferson L.S., Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR‐mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6, J. Biol. Chem., 274: 11647–11652, 1999. [DOI] [PubMed] [Google Scholar]
  • 44. Vary T.C., Jefferson L.S., Kimball S.R., Amino acid‐induced stimulation of translation initiation in rat skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 277: E1077–E1086, 1999. [DOI] [PubMed] [Google Scholar]
  • 45. Van Sluijters D.A., Dubbelhuis P.F., Blommaart E.F.C., Meijer A.J., Amino‐acid‐dependent signal transduction, Biochem. J., 351: 545–550, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Tinton S.A., Buc‐Calderon P.M., Hypoxia increases the association of 4E‐binding protein 1 with the initiation factor 4E in isolated rat hepatocytes, FEBS Lett., 446: 55–59, 1999. [DOI] [PubMed] [Google Scholar]
  • 47. Martin M.E., Muñoz F.M., Salinas M., Fando J.L., Ischaemia induces changes in the association of the binding protein 4E‐BP1 initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells, Biochem. J., 351: 327–334, 2000. [PMC free article] [PubMed] [Google Scholar]
  • 48. Lang C.H., Frost R.A., Kumar V., Vary T.C., Impaired myocardial protein synthesis induced by acute alcohol intoxication is associated with changes in eIF4F, Am. J. Physiol. Endocrinol. Metab., 279: E1029–E1038, 2000. [DOI] [PubMed] [Google Scholar]
  • 49. Gautsch T.A., Anthony J.C., Kimball S.R., Paul G.L., Layman D.K., Jefferson L.S., Availability of eIF4E regulates skeletal muscle protein synthesis during recovery from exercise, Am. J. Physiol. Cell Physiol., 274: C406–C414, 1998. [DOI] [PubMed] [Google Scholar]
  • 50. Shah O.J., Kimball S.R., Jefferson L.S., Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 278: E76–E82, 2000. [DOI] [PubMed] [Google Scholar]
  • 51. Shah O.J., Kimball S.R., Jefferson L.S., Glucocorticoids abate p70S6k and eIF4E function in L6 skeletal myoblasts, Am. J. Physiol. Endocrinol. Metab., 279: E74–E82, 2000. [DOI] [PubMed] [Google Scholar]
  • 52. Vary T.C., Kimball S.R., Effect of sepsis on eIE4E availability in skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 279: E1178–E1184, 2000. [DOI] [PubMed] [Google Scholar]
  • 53. Brewer J.W., Hendershot L.M., Sherr C.J., Diehl J.A., Mammalian unfolded protein response inhibits cyclin D1 translation and cell‐cycle progression, Proc. Natl. Acad. Sci. USA, 96: 8505–8510, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Hashemolhosseini S., Nagamine Y., Morley S.J., Desrivières S., Mercep L., Ferrari S., Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability, J. Biol. Chem., 273: 14424–14429, 1998. [DOI] [PubMed] [Google Scholar]
  • 55. Abid M.R., Li Y., Anthony C., De Benedetti A., Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication, J. Biol. Chem., 274: 35991–35998, 1999. [DOI] [PubMed] [Google Scholar]
  • 56. Vinals F., Chambard J.C., Pouyssegur J., p70 S6 kinase‐mediated protein synthesis is a critical step for vascular endothelial cell proliferation, J. Biol. Chem., 274: 26776–26782, 1999. [DOI] [PubMed] [Google Scholar]
  • 57. Staruch M.J., Sigal N.H., Dumont F.J., Differential effects of the immunosuppressive macrolides FK‐506 and rapamycin on activation‐induced T‐cell apoptosis, Int. J. Immunopharmacol., 13: 677–685, 1991. [DOI] [PubMed] [Google Scholar]
  • 58. McCarthy S.A., Cacchione R.N., Mainwaring M.S., Cairns J.S., The effects of immunosuppressive drugs on the regulation of activation‐induced apoptotic cell death in thymocytes, Transplant., 54: 543–547, 1992. [DOI] [PubMed] [Google Scholar]
  • 59. Luo H., Duguid W., Chen H., Maheu M., Wu J., The effect of rapamycin on T cell development in mice, Eur. J. Immunol., 24: 692–701, 1994. [DOI] [PubMed] [Google Scholar]
  • 60. Yao R., Cooper G.M., Growth factor‐dependent survival of rodent fibroblasts requires phosphatidylinositol 3‐kinase but is independent of pp7OS6K activity, Oncogene, 13: 343–351, 1996. [PubMed] [Google Scholar]
  • 61. Scheid M.P., Charlton L., Pelech S.L., Duronio V., Role of p70 S6 kinase in cytokine‐regulated hemopoietic cell survival, Biochem. Cell Biol., 74: 595–600, 1996. [DOI] [PubMed] [Google Scholar]
  • 62. Tee A.R., Proud C.G., Staurosporine inhibits phosphorylation of translational regulators linked to mTOR, Cell Death Differ., 8: 841–849, 2001. [DOI] [PubMed] [Google Scholar]
  • 63. Gottschalk A.R., Boise L.H., Thompson C.B., Quintans J., Identification of immunosuppressant‐induced apoptosis in a murine B‐cell lines and its prevention by bcl‐x but not bcl‐2, Proc. Natl. Acad. Sci. USA, 91: 7350–7354, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Shi Y., Frankel A., Radvanyi L.G., Penn L.Z., Miller R.G., Mills G.B., Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro, Cancer Res., 55: 1982–1988, 1995. [PubMed] [Google Scholar]
  • 65. Muthukkumar S., Ramesh T.M., Bondada S., Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells, Transplant., 60: 264–270, 1995. [DOI] [PubMed] [Google Scholar]
  • 66. Ishizuka T., Sakata N., Johnson G.L., Gelfand E.W., Terada N., Rapamycin potentiates dexamethasone‐induced apoptosis and inhibits JNK activity in lymphoblastoid cells, Biochem. Biophys. Res. Commun., 230: 386–391, 1997. [DOI] [PubMed] [Google Scholar]
  • 67. Migita K., Eguchi K., Ichinose Y., Kawabe Y., Tsukada T., Aoyagi T., Nagataki S., Effects of rapamycin on apoptosis of rheumatoid synovial cells, Clin. Exp. Immunol., 108: 199–203, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Hosoi H., Dilling M.B., Shikata T., Liu L.N., Shu L., Ashmun R.A., Germain G.S., Abraham R.T., Houghton P.J., Rapamycin causes poorly reversible inhibition of mTOR and induces p53‐independent apoptosis in human rhabdomyosarcoma cells, Cancer Res., 59: 886–894, 1999. [PubMed] [Google Scholar]
  • 69. Polunovsky V.A, Rosenwald I.B., Tan A.T., White J., Chiang L., Sonenberg N., Bitterman P.B., Translational control of programmed cell death: Eukaryotic translation initiation factor 4E blocks apoptosis in growth‐factor‐restricted fibroblasts with physiologically expressed or deregulated Myc, Mol. Cell. Biol., 16: 6573–6581, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Polunovsky V.A., Gingras A.C., Sonenberg N., Peterson M., Tan A., Rubins J.B., Manivel J.C, Bitterman P.B., Translational control of the antiapoptotic function of Ras, J. Biol. Chem., 275: 24776–24780, 2000. [DOI] [PubMed] [Google Scholar]
  • 71. Tan A., Bitterman P., Sonenberg N., Peterson M., Polunovsky V., Inhibition of Myc‐dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1, Oncogene, 19: 1437–1447, 2000. [DOI] [PubMed] [Google Scholar]
  • 72. Lazaris‐Karatzas A., Smith M.R., Frederickson R.M., Jaramillo M.L., Liu Y., Kung H., Sonenberg N., Ras mediates translation initiation factor 4E‐induced malignant transformation, Genes Dev., 6: 1631–1642, 1992. [DOI] [PubMed] [Google Scholar]
  • 73. Lazaris‐Karatzas A., Sonenberg N., The mRNA 5′ cap‐binding protein, eIF‐4E, cooperates with v‐myc or E1A in the transformation of primary rodent fibroblasts, Mol. Cell. Biol., 12: 1234–1238, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Graff J.R., Boghaert E.R., De Benedetti A., Tudor D.L., Zimmer C.C., Chan S.K., Zimmer S.G., Reduction of translation initiation factor 4E decreases the maligancy of ras‐transformed cloned rat embryo fibroblasts, Int. J. Cancer, 60: 255–263, 1995. [DOI] [PubMed] [Google Scholar]
  • 75. Zimmer S.G., Debenedetti A., Graff J.R., Translational control of malignancy: the mRNA cap‐binding protein, eIF‐4E, as a central regulator of tumor formation, growth, invasion and metastasis, Anticancer Res., 20: 1343–1351, 2000. [PubMed] [Google Scholar]
  • 76. Ptushkina M., Von der Haar T., Karim M.M., Hughes J.M.X., McCarthy J.E.G., Repressor binding to a dorsal regulatory site traps human eIF4E in a high cap‐affinity state, EMBO J., 18: 4068–4075, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Youtani T., Tomoo K., Ishida T., Miyoshi H., Miura K., Regulation of human eIF4E by 4E‐BP1: Binding analysis using surface plasmon resonance, Biochem. Mol. Biol. Int., 49: 27–31, 2000. [DOI] [PubMed] [Google Scholar]
  • 78. Duncan R.F., Song H.J.P., Striking multiplicity of eIF4E‐BP1 phosphorylated isoforms identified by 2D gel electrophoresis ‐ Regulation by heat shock, Eur. J. Biochem., 265: 728–743, 1999. [DOI] [PubMed] [Google Scholar]
  • 79. Yang D.Q., Brunn G.J., Lawrence J.C., Jr. , Mutational analysis of sites in the translational regulator, PHAS‐I, that are selectively phosphorylated by mTOR, FEBS Lett., 453: 387–390, 1999. [DOI] [PubMed] [Google Scholar]
  • 80. Gingras A.C., Gygi S.P., Raught B., Polakiewicz R.D., Abraham R.T., Hoekstra M.F., Aebersold R., Sonenberg N., Regulation of 4E‐BP1 phosphorylation: a novel two‐step mechanism, Genes Dev., 13: 1422–1437, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Mothe‐Satney I., Brunn G.J., McMahon L.P., Capaldo C.T., Abrahams R.T., Lawrence J.C., Jr. , Mammalian target of rapamycin‐dependent phosphorylation of PHAS‐I in four (S/T)P sites detected by phospho‐specific antibodies, J. Biol. Chem., 275: 33836–33843, 2000. [DOI] [PubMed] [Google Scholar]
  • 82. Mothe‐Satney I., Yang D.Q., Fadden P., Haystead T.A.J., Lawrence J.C., Jr. , Multiple mechanisms control phosphorylation of PHAS‐I in five (S/T)P sites that govern translational repression, Mol. Cell. Biol., 20: 3558–3567, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Khaleghpour K., Pyronnet S., Gingras A.C., Sonenberg N., Translational homeostasis: Eukaryotic translation initiation factor 4E control of 4E‐binding protein 1 and p70 S6 kinase activities, Mol. Cell. Biol., 19: 4302–4310, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Cutler N.S., Heitman J., Cardenas M.E., TOR kinase homologs function in a signal transduction pathway that is conserved from yeast to mammals, Mol. Cell. Endocrinol., 155: 135–142, 1999. [DOI] [PubMed] [Google Scholar]
  • 85. Schmelzle T., Hall M.N., TOR, a central controller of cell growth, Cell, 103: 253–262, 2000. [DOI] [PubMed] [Google Scholar]
  • 86. Rohde J., Heitman J., Cardenas M.E., The TOR kinases link nutrient sensing to cell growth, J. Biol. Chem., 276: 9583–9586, 2001. [DOI] [PubMed] [Google Scholar]
  • 87. Gingras A‐C., Raught B., Sonenberg N., Regulation of translation initiation by FRAP/mTOR, Genes Dev., 15: 807–826, 2001. [DOI] [PubMed] [Google Scholar]
  • 88. Raught B., Gingras A‐C., Sonenberg N., The target of rapamycin (TOR) proteins, Proc. Natl. Acad. Sci. USA, 98: 7037–7044, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Gingras A‐C., Raught B., Sonenberg N., Control of translation by the target of rapamycin proteins In: Rhoads R.E., ed., Signaling pathways for translation: Stress, calcium, and rapamycin, Springer, Berlin , 2001. [DOI] [PubMed] [Google Scholar]
  • 90. Wang L.J., Wang X.M., Proud C.G., Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin‐sensitive steps, Am. J. Physiol. Heart Circ. Physiol., 278: H1056–H1068, 2000. [DOI] [PubMed] [Google Scholar]
  • 91. Kimball S.R., Horetsky R.L., Jefferson L.S., Signal transduction pathways involved in the regulation of protein synthesis by insulin in L6 myoblasts, Am. J. Physiol. Cell Physiol., 274: C221–C228, 1998. [DOI] [PubMed] [Google Scholar]
  • 92. Wang X.M., Campbell L.E., Miller C.M., Proud C.G., Amino acid availability regulates p70 S6 kinase and multiple translation factors, Biochem. J., 334: 261–267, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Hara K., Yonezawa K., Weng Q.P., Kozlowski M.T., Belham C., Avruch J., Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF‐4E BP1 through a common effector mechanism, J. Biol. Chem., 273: 14484–14494, 1998. [DOI] [PubMed] [Google Scholar]
  • 94. Xu G., Kwon G., Marshall C.A., Lin T.A., Lawrence J.C., Jr. , McDaniel M.L., Branched‐chain amino acids are essential in the regulation of PHAS‐I and p70 S6 kinase by pancreatic β‐cells ‐ A possible role in protein translation and mitogenic signaling, J. Biol. Chem., 273: 28178–28184, 1998. [DOI] [PubMed] [Google Scholar]
  • 95. Shigemitsu K., Tsujishita Y., Hara K., Nanahoshi M., Avruch J., Yonezawa K., Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways ‐ Possible involvement of autophagy in cultured hepatoma cells, J. Biol. Chem., 274: 1058–1065, 1999. [DOI] [PubMed] [Google Scholar]
  • 96. Anthony J.C., Yoshizawa F., Anthony T.G., Vary T.C., Jefferson L.S., Kimball S.R., Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin‐sensitive pathway, J. Nutr., 130: 2413–2419, 2000. [DOI] [PubMed] [Google Scholar]
  • 97. Kimball S.R., Jefferson L.S., Nguyen H.V., Suryawan A., Bush J.A., Davis T.A., Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR‐dependent process, Am. J. Physiol. Endocrinol. Metab., 279: E1080–E1087, 2000. [DOI] [PubMed] [Google Scholar]
  • 98. Loreni F., Thomas G., Amaldi F., Transcription inhibitors stimulate translation of 5′ TOP mRNAs through activation of S6 kinase and the mTOR/FRAP signalling pathway, Eur. J. Biochem., 267: 6594–6601, 2000. [DOI] [PubMed] [Google Scholar]
  • 99. Dufner A., Thomas G., Ribosomal S6 kinase signaling and the control of translation, Exp. Cell Res., 253: 100–109, 1999. [DOI] [PubMed] [Google Scholar]
  • 100. Shah O.J., Anthony J.C., Kimball S.R., Jefferson L.S., 4E‐BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle, Am. J. Physiol. Endocrinol. Metab., 279: E715–E729, 2000. [DOI] [PubMed] [Google Scholar]
  • 101. Meyuhas O., Synthesis of the translational apparatus is regulated at the translational level, Eur. J. Biochem., 267: 6321–6330, 2000. [DOI] [PubMed] [Google Scholar]
  • 102. Anthony T.G., Anthony J.C., Yoshizawa F., Kimball S.R., Jefferson L.S., Oral administration of leucine stimulates ribosomal protein mRNA translation but not global rates of protein synthesis in the liver of rats, J. Nutr., 131: 1171–1176, 2001. [DOI] [PubMed] [Google Scholar]
  • 103. Raught B., Gingras A.C., Gygi S.P., Imataka H., Morino S., Gradi A., Aebersold R., Sonenberg N., Serum‐stimulated, rapamycin‐sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI, EMBO J., 19: 434–444, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Powers T., Walter P., Regulation of ribosome biogenesis by the rapamycin‐sensitive TOR‐signaling pathway in Saccharomyces cerevisiae, Mol. Biol. Cell, 10: 987–1000, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105. Dufner A., Andjelkovic M., Burgering B.M.T., Hemmings B.A., Thomas G., Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E‐binding protein 1 phosphorylation, Mol. Cell. Biol., 19: 4525–4534, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Miron M., Verdu J., Lachance P.E.D., Birnbaum M.J., Lasko P.F., Sonenberg N., The translational inhibitor 4E‐BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila, Nature Cell Biol., 3: 596–601, 2001. [DOI] [PubMed] [Google Scholar]
  • 107. Peyrollier K., Hajduch E., Blair A.S., Hyde R., Hundal H.S., L‐leucine availability regulates phosphatidylinositol 3‐ kinase, p70 S6 kinase and glycogen synthase kinase‐3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L‐leucine‐ induced up‐regulation of System A amino acid transport, Biochem. J., 350: 361–368, 2000. [PMC free article] [PubMed] [Google Scholar]
  • 108. Bhandari B.K., Feliers D., Duraisamy S., Stewart J.L., Gingras A‐C., Abboud H.E., Choudhury G.G., Sonenberg N., Kasinath B.S., Insulin regulation of protein translation repressor 4E‐BP1, an eIF4E‐binding protein, in renal epithelial cells, Kidney Int., 59: 866–875, 2001. [DOI] [PubMed] [Google Scholar]
  • 109. Pham P.T.T., Heydrick S.J., Fox H.L., Kimball S.R., Jefferson L.S., Jr. , Lynch C.J., Assessment of cell‐signaling pathways in the regulation of mammalian target of rapamycin (mTOR) by amino acids in rat adipocytes, J. Cell. Biochem., 79: 427–441, 2000. [DOI] [PubMed] [Google Scholar]
  • 110. Iiboshi Y., Papst P.J., Kawasome H., Hosoi H., Abraham R.T., Houghton P.J., Terada N., Amino acid‐dependent control of p70(s6k). Involvement of tRNa aminoacylation in the regulation, J. Biol. Chem., 274: 1092–1099, 1999. [DOI] [PubMed] [Google Scholar]
  • 111. Campbell L.E., Wang X.M., Proud C.G., Nutrients differentially regulate multipl translation factors and their control by insulin, Biochem. J., 344: 433–441, 1999. [PMC free article] [PubMed] [Google Scholar]
  • 112. Lawrence J.C., Fadden P., Haystead T. A., Lin T.A., PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation, Adv Enzyme Regul, 37: 239–267, 1997. [DOI] [PubMed] [Google Scholar]
  • 113. Vary T.C., Jefferson L.S., Kimball S.R., Role of eIF4E in stimulation of protein synthesis by IGFI in perfused rat skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 278: E58–E64, 2000. [DOI] [PubMed] [Google Scholar]
  • 114. Franek F., Sramkova K., Protection of B lymphocyte hybridoma against starvation‐induced apoptosis: survival‐signal role of some amino acids, Immunol. Lett., 52: 139–144, 1996. [DOI] [PubMed] [Google Scholar]
  • 115. Franek F., Srámková K., Cell suicide in starving hybridoma culture: Survival‐signal effect of some amino acids, Cytotechnology, 23: 231–239, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Simpson N.H., Singh R.P., Perani A., Goldenzon C., Al‐Rubeai M., In hybridoma cultures, deprivation of any single amino acid leads to apoptotic death, which is suppressed by the expression of the bcl‐2 gene, Biotechnol. Bioeng., 59: 90–98, 1998. [DOI] [PubMed] [Google Scholar]
  • 117. Herbert T.P., Kilhams G.R., Batty I.H., Proud C.G., Distinct signalling pathways mediate insulin and phorbol ester‐stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells, J. Biol. Chem., 275: 11249–11256, 2000. [DOI] [PubMed] [Google Scholar]
  • 118. Kumar V., Pandey P., Sabatini D., Kumar M., Majumder P.K., Bharti A., Carmichael G., Kufe D., Kharbanda S., Functional interaction between RAFT1/FRAP/mTOR and protein kinase Cδ in the regulation of cap‐dependent initiation of translation, EMBO J., 19: 1087–1097, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119. Kim J.E., Chen J., Cytoplasmic‐nuclear shuttling of FKBP12‐rapamycin‐associated protein is involved in rapamycin‐sensitive signaling and translation initiation, Proc. Natl. Acad. Sci. USA, 97: 14340–14345, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120. Kumar V., Sabatini D., Pandey P., Gingras A.C., Majumder P.K., Kumar M., Yuan Z.M., Carmichael G., Weichselbaum R., Sonenberg N., Kufe D., Kharbanda S., Regulation of the rapamycin and FKBP‐target 1/mammalian target of rapamycin and cap‐dependent initiation of translation by the c‐Abl protein‐tyrosine kinase, J. Biol. Chem., 275: 10779–10787, 2000. [DOI] [PubMed] [Google Scholar]
  • 121. Jiang Y‐P., Ballou L.M., Lin R.Z., Rapamycin‐insensitive regulation of 4E‐BP1 in regenerating rat liver, J. Biol. Chem., 276: 10943–10951, 2001. [DOI] [PubMed] [Google Scholar]
  • 122. Heesom K.J., Denton R.M., Dissociation of the eukaryotic initiation factor‐4E/4E‐BP1 complex involves phosphorylation of 4E‐BP1 by an mTOR‐associated kinase, FEBS Lett., 457: 489–493, 1999. [DOI] [PubMed] [Google Scholar]
  • 123. Heesom K.J., Avison M.B., Diggle T.A., Denton R.M., Insulin‐stimulated kinase from rat fat cells that phosphorylates initiation factor 4E‐binding protein 1 on the rapamycin‐insensitive site (serine‐111), Biochem. J., 336: 39–48, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124. Yang D‐Q., Kastan M.B., Participation of ATM in insulin signalling through phosphorylation of eIF‐4E‐binding protein 1, Nature Cell Biol., 2: 893–898, 2000. [DOI] [PubMed] [Google Scholar]
  • 125. Nanahoshi M., Nishiuma T., Tsujishita Y., Hara K., Inui S., Sakaguchi N., Yonezawa K., Regulation of protein phosphatase 2A catalytic activity by alpha4 protein and its yeast homolog Tap42, Biochem. Biophys. Res. Commun., 251: 520–526, 1998. [DOI] [PubMed] [Google Scholar]
  • 126. Peterson R.T., Desai B.N., Hardwick J.S., Schreiber S.L., Protein phosphatase 2A interacts with the 70‐kDa S6 kinase and is activated by inhibition of FKBP12‐rapamycin‐associated protein, Proc. Natl. Acad. Sci. USA, 96: 4438–4442, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Pham F.H., Sugden P.H., Clerk A., Regulation of protein kinase B and 4E‐BP1 by oxidative stress in cardiac myocytes, Circ. Res., 86: 1252–1258, 2000. [DOI] [PubMed] [Google Scholar]
  • 128. Lin T.A., Lawrence J.C., Jr. , Control of PHAS‐I phosphorylation in 3T3‐L1 adipocytes: Effects of inhibiting protein phosphatases and the p70S6K signalling pathway, Diabetologia, 40 Suppl. 2: S18‐S24, 1997. [DOI] [PubMed] [Google Scholar]
  • 129. Peterson R.T., Beal P.A., Comb M.J., Schreiber S.L., FKBP12‐rapamycin‐associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions, J. Biol. Chem., 275: 7416–7423, 2000. [DOI] [PubMed] [Google Scholar]
  • 130. Clemens M.J., Elia A., The double‐stranded RNA‐dependent protein kinase PKR: Structure and function, J. Interferon Cytokine Res., 17: 503–524, 1997. [DOI] [PubMed] [Google Scholar]
  • 131. Williams B.R.G., PKR; a sentinel kinase for cellular stress, Oncogene, 18: 6112–6120, 1999. [DOI] [PubMed] [Google Scholar]
  • 132. Xu Z., Williams B.R.G., The B56α regulatory subunit of protein phosphatase 2A is a target for regulation by double‐stranded RNA‐dependent protein kinase PKR, Mol. Cell. Biol., 20: 5285–5299, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133. Basu S., Kolesnick R., Stress signals for apoptosis: ceramide and c‐Jun kinase, Oncogene, 17: 3277–3285, 1998. [DOI] [PubMed] [Google Scholar]
  • 134. Sawada N., Nakashima S., Banno Y., Yamakawa H., Hayashi K., Takenaka K., Nishimura Y., Sakai N., Nozawa Y., Ordering of ceramide formation, caspase activation, and Bax/Bcl‐2 expression during etoposide‐induced apoptosis in C6 glioma cells, Cell Death Differ., 7: 761–772, 2000. [DOI] [PubMed] [Google Scholar]
  • 135. Ruvolo P.P., Gao F., Blalock W.L., Deng X., May W.S., Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX, J. Biol. Chem. , 2001. [DOI] [PubMed]
  • 136. Sortino M.A., Condorelli F., Vancheri C., Canonico P.L., Tumor necrosis factor‐α induces apoptosis in immortalized hypothalamic neurons: Involvement of ceramide‐generating pathways, Endocrinology, 140: 4841–4849, 1999. [DOI] [PubMed] [Google Scholar]
  • 137. Mendez R., Myers M.G., Jr. , White M.F., Rhoads R.E., Stimulation of protein synthesis, eukaryotic translation initiation factor 4Ephosphorylation, and PHAS‐I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3‐kinase, Mol. Cell. Biol., 16: 2857–2864, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138. Marx S.O., Marks A.R., Cell cycle progression and proliferation despite 4BP‐1 dephosphorylation, Mol. Cell. Biol., 19: 6041–6047, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139. Saghir A.N., Tuxworth W.J., Hagedorn C.H., McDermott P.J., Modifications of eukaryotic initiation factor 4F (eIF4F) in adult cardiocytes by adenoviral gene transfer: differential effects on eIF4F activity and total protein synthesis rates, Biochem. J., 356: 557–566, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140. Morley S.J., The regulation of eIF4F during cell growth and cell death In: Rhoads R.E., ed., Signaling pathways for translation: Stress, calcium, and rapamycin, Springer, Berlin , 2001. [Google Scholar]
  • 141. Koromilas A.E., Lazaris‐Karatzas A., Sonenberg N., mRNAs containing extensive secondary structure in their 5′ non‐coding region translate efficiently in cells overexpressing initiation factor eIF‐4E, EMBO J., 11: 4153–4158, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 142. Sachs A.B., Sarnow P., Hentze M.W., Starting at the beginning, middle, and end: Translation initiation in eukaryotes, Cell, 89: 831–838, 1997. [DOI] [PubMed] [Google Scholar]
  • 143. Imataka H., Gradi A., Sonenberg N., A newly identified N‐terminal amino acid sequence of human eIF4G binds poly(A)‐binding protein and functions in poly(A)‐ dependent translation, EMBO J., 17: 7480–7489, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 144. Keiper B.D., Rhoads R.E., Cap‐independent translation initiation in Xenopus oocytes, Nucleic Acids Res., 25: 395–402, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 145. Novoa I., Carrasco L., Cleavage of eukaryotic translation initiation factor 4G by exogenously added hybrid proteins containing poliovirus 2Apro in HeLa cells: Effects on gene expression, Mol. Cell. Biol., 19: 2445–2454, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 146. Duncan R.F., Milburn S.C., Hershey J.W.B., Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF4F suggest a role in translational control, J. Biol. Chem., 262: 380–388, 1987. [PubMed] [Google Scholar]
  • 147. Berset C., Trachsel H., Altmann M., The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 95: 4264–4269, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 148. Rau M., Ohlmann T., Morley S.J., Pain V.M., A reevaluation of the cap‐binding protein, eIF4E, as a rate‐limiting factor for initiation of translation in reticulocyte lysate, J. Biol. Chem., 271: 8983–8990, 1996. [DOI] [PubMed] [Google Scholar]
  • 149. Marissen W.E., Lloyd R.E., Eukaryotic translation initiation factor 4G is targeted for proteolytic cleavage by caspase 3 during inhibition of translation in apoptotic cells, Mol. Cell. Biol., 18: 7565–7574, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES