Search tips
Search criteria 


Logo of molcellbJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. 1996 November; 16(11): 6573–6581.
PMCID: PMC231659

Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc.


There is increasing evidence that cell cycle transit is potentially lethal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupling cell cycle transit to survival remain undefined. Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate both proliferative and survival signaling. Overexpression of eIF4E completely substituted for serum or individual growth factors in preserving the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (Ser-53 changed to Ala) defective in mediating its growth-factor-regulated functions was also defective in its survival signaling. Survival signaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression of the apoptosis antagonists Bcl-2 and Bcl-XL. In addition, the execution apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact. Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enforced expression of Myc. In contrast, activation of Ha-Ras, which is required for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leading to survival and cell cycle progression are distinct. This dual signaling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.

Full Text

The Full Text of this article is available as a PDF (1.7M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Almasan A, Yin Y, Kelly RE, Lee EY, Bradley A, Li W, Bertino JR, Wahl GM. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5436–5440. [PubMed]
  • Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene. 1991 Oct;6(10):1915–1922. [PubMed]
  • Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nuñez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. [PubMed]
  • Bommer UA, Lazaris-Karatzas A, De Benedetti A, Nürnberg P, Benndorf R, Bielka H, Sonenberg N. Translational regulation of the mammalian growth-related protein P23: involvement of eIF-4E. Cell Mol Biol Res. 1994;40(7-8):633–641. [PubMed]
  • Brooks RF. Continuous protein synthesis is required to maintain the probability of entry into S phase. Cell. 1977 Sep;12(1):311–317. [PubMed]
  • Cherney BW, Bhatia K, Tosato G. A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12967–12971. [PubMed]
  • Evan GI, Brown L, Whyte M, Harrington E. Apoptosis and the cell cycle. Curr Opin Cell Biol. 1995 Dec;7(6):825–834. [PubMed]
  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. [PubMed]
  • Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992 Oct 8;359(6395):554–556. [PubMed]
  • Frederickson RM, Montine KS, Sonenberg N. Phosphorylation of eukaryotic translation initiation factor 4E is increased in Src-transformed cell lines. Mol Cell Biol. 1991 May;11(5):2896–2900. [PMC free article] [PubMed]
  • Frederickson RM, Mushynski WE, 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. 1992 Mar;12(3):1239–1247. [PMC free article] [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Graves LM, Bornfeldt KE, Argast GM, Krebs EG, Kong X, Lin TA, Lawrence JC., Jr cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7222–7226. [PubMed]
  • Harrington EA, Bennett MR, Fanidi A, Evan GI. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994 Jul 15;13(14):3286–3295. [PubMed]
  • Haystead TA, Haystead CM, Hu C, Lin TA, Lawrence JC., Jr Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem. 1994 Sep 16;269(37):23185–23191. [PubMed]
  • Hernández G, Sierra JM. Translation initiation factor eIF-4E from Drosophila: cDNA sequence and expression of the gene. Biochim Biophys Acta. 1995 Apr 26;1261(3):427–431. [PubMed]
  • Hiebert SW, Packham G, Strom DK, Haffner R, Oren M, Zambetti G, Cleveland JL. E2F-1:DP-1 induces p53 and overrides survival factors to trigger apoptosis. Mol Cell Biol. 1995 Dec;15(12):6864–6874. [PMC free article] [PubMed]
  • Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6875–6879. [PubMed]
  • Hockenbery DM. bcl-2, a novel regulator of cell death. Bioessays. 1995 Jul;17(7):631–638. [PubMed]
  • Ishizaki Y, Cheng L, Mudge AW, Raff MC. Programmed cell death by default in embryonic cells, fibroblasts, and cancer cells. Mol Biol Cell. 1995 Nov;6(11):1443–1458. [PMC free article] [PubMed]
  • Jewell AP, Lydyard PM, Worman CP, Giles FJ, Goldstone AH. Growth factors can protect B-chronic lymphocytic leukaemia cells against programmed cell death without stimulating proliferation. Leuk Lymphoma. 1995 Jun;18(1-2):159–162. [PubMed]
  • Joshi B, Cai AL, Keiper BD, Minich WB, Mendez R, Beach CM, Stepinski J, Stolarski R, Darzynkiewicz E, Rhoads RE. Phosphorylation of eukaryotic protein synthesis initiation factor 4E at Ser-209. J Biol Chem. 1995 Jun 16;270(24):14597–14603. [PubMed]
  • Joshi-Barve S, Rychlik W, Rhoads RE. Alteration of the major phosphorylation site of eukaryotic protein synthesis initiation factor 4E prevents its association with the 48 S initiation complex. J Biol Chem. 1990 Feb 15;265(5):2979–2983. [PubMed]
  • Kim HR, Upadhyay S, Li G, Palmer KC, Deuel TF. Platelet-derived growth factor induces apoptosis in growth-arrested murine fibroblasts. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9500–9504. [PubMed]
  • Klein PS, Melton DA. Induction of mesoderm in Xenopus laevis embryos by translation initiation factor 4E. Science. 1994 Aug 5;265(5173):803–806. [PubMed]
  • Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature. 1990 Jun 7;345(6275):544–547. [PubMed]
  • Lazaris-Karatzas A, Smith MR, Frederickson RM, Jaramillo ML, Liu YL, Kung HF, Sonenberg N. Ras mediates translation initiation factor 4E-induced malignant transformation. Genes Dev. 1992 Sep;6(9):1631–1642. [PubMed]
  • 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. 1992 Mar;12(3):1234–1238. [PMC free article] [PubMed]
  • Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N, Lawrence JC., Jr PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science. 1994 Oct 28;266(5185):653–656. [PubMed]
  • Lowe SW, Ruley HE. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 1993 Apr;7(4):535–545. [PubMed]
  • Mader S, Sonenberg N. Cap binding complexes and cellular growth control. Biochimie. 1995;77(1-2):40–44. [PubMed]
  • Makkinje A, Xiong H, Li M, Damuni Z. Phosphorylation of eukaryotic protein synthesis initiation factor 4E by insulin-stimulated protamine kinase. J Biol Chem. 1995 Jun 16;270(24):14824–14828. [PubMed]
  • Meikrantz W, Gisselbrecht S, Tam SW, Schlegel R. Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3754–3758. [PubMed]
  • Miyagi Y, Sugiyama A, Asai A, Okazaki T, Kuchino Y, Kerr SJ. Elevated levels of eukaryotic translation initiation factor eIF-4E, mRNA in a broad spectrum of transformed cell lines. Cancer Lett. 1995 May 8;91(2):247–252. [PubMed]
  • Morley SJ, Traugh JA. Stimulation of translation in 3T3-L1 cells in response to insulin and phorbol ester is directly correlated with increased phosphate labelling of initiation factor (eIF-) 4F and ribosomal protein S6. Biochimie. 1993;75(11):985–989. [PubMed]
  • Packham G, Cleveland JL. c-Myc and apoptosis. Biochim Biophys Acta. 1995 Jul 28;1242(1):11–28. [PubMed]
  • Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762–767. [PubMed]
  • Polunovsky VA, Chen B, Henke C, Snover D, Wendt C, Ingbar DH, Bitterman PB. Role of mesenchymal cell death in lung remodeling after injury. J Clin Invest. 1993 Jul;92(1):388–397. [PMC free article] [PubMed]
  • Polunovsky VA, Wendt CH, Ingbar DH, Peterson MS, Bitterman PB. Induction of endothelial cell apoptosis by TNF alpha: modulation by inhibitors of protein synthesis. Exp Cell Res. 1994 Oct;214(2):584–594. [PubMed]
  • Preston GA, Lang JE, Maronpot RR, Barrett JC. Regulation of apoptosis by low serum in cells of different stages of neoplastic progression: enhanced susceptibility after loss of a senescence gene and decreased susceptibility after loss of a tumor suppressor gene. Cancer Res. 1994 Aug 1;54(15):4214–4223. [PubMed]
  • Raff MC. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. [PubMed]
  • Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed]
  • Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. [PMC free article] [PubMed]
  • Rhoads RE. Regulation of eukaryotic protein synthesis by initiation factors. J Biol Chem. 1993 Feb 15;268(5):3017–3020. [PubMed]
  • Rinker-Schaeffer CW, Austin V, Zimmer S, Rhoads RE. Ras transformation of cloned rat embryo fibroblasts results in increased rates of protein synthesis and phosphorylation of eukaryotic initiation factor 4E. J Biol Chem. 1992 May 25;267(15):10659–10664. [PubMed]
  • Rosenwald IB. Growth factor-independent expression of the gene encoding eukaryotic translation initiation factor 4E in transformed cell lines. Cancer Lett. 1995 Nov 27;98(1):77–82. [PubMed]
  • Goddard DH, Bomalaski JS, Lipper S, Shorr RG, Clark MA. Phospholipase A2-mediated inflammation induces regression of malignant gliomas. Cancer Lett. 1996 Apr 19;102(1-2):1–6. [PubMed]
  • Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem. 1995 Sep 8;270(36):21176–21180. [PubMed]
  • Rosenwald IB, Lazaris-Karatzas A, Sonenberg N, Schmidt EV. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol. 1993 Dec;13(12):7358–7363. [PMC free article] [PubMed]
  • Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6175–6178. [PubMed]
  • Scher CD, Young SA, Locatell KL. Control of cytolysis of BALB/c-3T3 cells by platelet-derived growth factor: a model system for analyzing cell death. J Cell Physiol. 1982 Nov;113(2):211–218. [PubMed]
  • Schwarze MM, Hawley RG. Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res. 1995 Jun 1;55(11):2262–2265. [PubMed]
  • Shantz LM, Pegg AE. Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res. 1994 May 1;54(9):2313–2316. [PubMed]
  • Shimizu Y, Van Seventer GA, Siraganian R, Wahl L, Shaw S. Dual role of the CD44 molecule in T cell adhesion and activation. J Immunol. 1989 Oct 15;143(8):2457–2463. [PubMed]
  • Slack RS, Skerjanc IS, Lach B, Craig J, Jardine K, McBurney MW. Cells differentiating into neuroectoderm undergo apoptosis in the absence of functional retinoblastoma family proteins. J Cell Biol. 1995 May;129(3):779–788. [PMC free article] [PubMed]
  • Smith MR, Jaramillo M, Liu YL, Dever TE, Merrick WC, Kung HF, Sonenberg N. Translation initiation factors induce DNA synthesis and transform NIH 3T3 cells. New Biol. 1990 Jul;2(7):648–654. [PubMed]
  • Solary E, Bertrand R, Pommier Y. Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL-60 cells. Leuk Lymphoma. 1994 Sep;15(1-2):21–32. [PubMed]
  • Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. [PubMed]
  • Taher A, Yanai N, Obinata M. Properties of incompletely immortalized cell lines generated from a line established from temperature-sensitive SV40 T-antigen gene transgenic mice. Exp Cell Res. 1995 Aug;219(2):332–338. [PubMed]
  • Tamm I, Kikuchi T. Insulin-like growth factor-1 (IGF-1), insulin, and epidermal growth factor (EGF) are survival factors for density-inhibited, quiescent Balb/c-3T3 murine fibroblasts. J Cell Physiol. 1990 Jun;143(3):494–500. [PubMed]
  • Tamm I, Kikuchi T. Activation of signal transduction pathways protects quiescent Balb/c-3T3 fibroblasts against death due to serum deprivation. J Cell Physiol. 1991 Jul;148(1):85–95. [PubMed]
  • Tamm I, Kikuchi T, Zychlinsky A. Acidic and basic fibroblast growth factors are survival factors with distinctive activity in quiescent BALB/c 3T3 murine fibroblasts. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3372–3376. [PubMed]
  • Wagner AJ, Small MB, Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Mol Cell Biol. 1993 Apr;13(4):2432–2440. [PMC free article] [PubMed]
  • Wu X, Levine AJ. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3602–3606. [PubMed]
  • Wyllie AH, Rose KA, Morris RG, Steel CM, Foster E, Spandidos DA. Rodent fibroblast tumours expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression. Br J Cancer. 1987 Sep;56(3):251–259. [PMC free article] [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)