Abstract
Ectopically expressed eukaryotic translation initiation factor 4E (eIF4E) stimulates cell proliferation, suppresses apoptosis in growth factor restricted cells, and induces malignant transformation in primary rodent fibroblasts when coexpressed with protooncogene myc. We report here that eIF4E rescued rat embryo fibroblasts ectopically expressing c-Myc (REF/Myc) from genotoxic and non-genotoxic cytostatic drugs and identify cyclin D1 as a downstream effector in the antiapoptotic mechanism. In clones of REF/Myc ectopically expressing eIF4E, resistance to apoptosis paralleled steady state levels of cyclin D1. Stable expression of cyclin D1 in REF/Myc inhibited apoptosis in response to a broad range of cell cycle specific cytostatic agents. Partial loss-of-cyclin D1 function in REF/Myc ectopically expressing eIF4E (REF/Myc/4E) significantly increased chemosensitivity; either soluble antisense cyclin D1 oligomers or transfection with a dominant negative cyclin D1 mutant that prevents translocation of cyclin D-dependent kinases to the nucleus, significantly blunted the antiapoptotic effect of eIF4E. These data directly link eIF4E rescue from cytostatic drugs to cyclin D1. Since overexpression of eIF4E and cyclin D1 is observed in many aggressive forms of chemoresistant cancers, these findings provide insight into possible mechanisms responsible for this biological behavior.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ajchenbaum F, Ando K, DeCaprio J and Griffin JD . 1993 J Biol Chem 268: 4113–4119
Albanese C, D'Amico M, Reutens AT, Fu M, Watanabe GG, Lee RJ, Kitsis RN, Henglein B, Avantaggiati M, Somasundaram K, Thimmapaya B and Pestell R . 1999 J Biol Chem 274: 34186–34195
Ando K, Ajchenbaum-Cymbalista F and Griffin JD . 1993 Proc Natl Acad Sci USA 9: 9571–9575
Busser JD, Geldmacher S and Herrup K . 1998 J Neurosci 18: 2801–2807
Canman CE and Kastan MB . 1995 Sem Cancer Biol 6: 17–25
Dang CV . 1999 Mol Cell Biol 19: 1–11
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . 1997 Cell 91: 231–241
De Benedetti A and Harris AL . 1999 Int J Biochem Cell Biol 3: 59–72
de Jong JS, van Diest PJ, Michalides RJ, van der Valk P, Meijer CJ and Baak JP . 1998 Mol Pathol 51: 30–34
del Peso L, Gonzales-Garcia M, Page C, Herrera R and Nunez G . 1997 Science 278: 687–689
Diehl JA and Sherr CJ . 1997 Mol Cell Biol 17: 7362–7374
Driscoll B, Buckley S, Barsky L, Weinberg K, Anderson KD and Warburton D . 1999 Am J Physiol 20: L679–L689
Duttaroy A, Qian JF, Smith JS and Wang E . 1997 J Cell Biochem 64: 434–446
Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ and Hancock DC . 1992 Cell 69: 19–128
Fan G and Steer CJ . 1999 Apoptosis 4: 21–29
Franke TF, Kaplan DR, Cantley LC and Toker A . 1997 Science 27: 655–668
Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N and Beger HG . 1997 Cancer Res 57: 1634–1637
Giardina SF, Cheung NS, Reid MT and Beart PM . 1998 J Neurochem 71: 1325–1328
Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N and Hay N . 1998 Genes Dev 12: 502–513
Gonzalez-Garcia A, Merida I, Martinez AC and Carrer AC . 1997 J Biol Chem 272: 10220–10226
Gradi A, Imataka H, Svitkin YV, Rom E, Raught B, Morino S and Sonenberg N . 1998 Mol Cell Biol 18: 334–342
Green DR, McGahon A and Martin SJ . 1996 J Cell Biochem 60: 33–38
Guegan C, Levy V, David JP, Ajchembaum-Cymbalista F and Sola B . 1997 NeuroReport 8: 1003–1007
Han EKH, Ng SC, Arger N, Begemann M and Weinstein IB . 1999 Apoptotis 4: 213–219
Harrington EA, Bennett MR, Fanidi A and Evan GI . 1994 EMBO J 13: 3286–3295
Hiyama H and Reeves SA . 1999 Cell Death Differ 6: 565–569
Hsieh J-K, Chan FS, O'Connor DJ, Mittnacht S, Zhong S and Lu X . 1999 Mol Cell 3: 181–193
Hung WC, Huang JS and Chuang LY . 1996 Biochem Biophys Res Comm 220: 719–723
Hunter T and Pines J . 1994 Cell 79: 573–582
Inoue K and Sherr CJ . 1998 Mol Cell Biol 18: 1590–1600
Katayose Y, Kim M, Rakkar ANS, Liu Z, Cowan KH and Seth P . 1997 Cancer Res 57: 5441–5445
Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN and Hay N . 1997 Genes Dev 11: 701–713
Kornmann M, Arber N and Korc M . 1998 J Clin Invest 101: 344–352
Kotelnikov VM, Coon IV JS, Mundle S, Kelanic S, LaFollette S, Taylor IV S, Hutchinson J, Panje W, Caldarelli DD and Preisler HD . 1997 Clin Cancer Res 3: 95–101
Kranenburg O, van der Eb AJ and Zantema A . 1996 EMBO J 15: 46–54
Lazaris-Karatzas A and Sonenberg N . 1992 Mol Cell Biol 12: 1234–1238
Li Y, Chopp M, Powers C and Jiang N . 1997 Brain Res 765: 301–312
Lin T-A, Kong X, Haystead TAJ, Pause A, Belsham G, Sonenberg N and Lawrence Jr JC . 1994 Science 266: 653–656
Liu W, Bi X, Tocco G, Baudy M and Schreiber SS . 1996 NeuroReport 7: 2785–2789
Lungberg AS and Weinberg RA . 1999 Eur J Cancer 25: 531–539
Ma C, Papermaster D and Cepko CL . 1998 Proc Natl Acad Sci USA 95: 9938–9943
Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato JY . 1994 Mol Cell Biol 14: 2066–2076
Mommers EC, Van Diest PJ, Leonhart AM, Meijer CJ and Baak JP . 1998 Hum Pathol 29: 1539–1545
Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M and Ewen ME . 1997 Mol Cell Biol 17: 5338–5347
Packham G and Cleveland JL . 1995 Microbiol Immunol 194: 283–290
Pardo FS, Su M and Borek C . 1996 Somat Cell Mol Genet 22: 135–144
Pause A, Belsham GJ, Gingras A-C, Donze O, Lin T-A, Lawrence Jr JC and Sonenberg N . 1994 Nature 371: 762–767
Phillips AC, Ernst MK, Bates S, Rice NR and Vousden KH . 1999 Mol Cell 4: 771–781
Polunovsky VA, Chen, Henke C, Snover D, Wendt C, Ingbar DH and Bitterman PB . 1993 J Clin Invest 92: 388–397
Polunovsky VA, Rosenwald IB, Tan AT, White J, Chiang L, Sonenberg N and Bitterman PB . 1996 Mol Cell Biol 16: 6573–6581
Polunovsky VA, Wendt CH, Ingbar DH, Peterson MN and Bitterman PB . 1994 Exp Cell Res 214: 584–594
Poon RYC, Toyoshima H and Hunter T . 1995 Mol Biol Cell 6: 1197–1213
Postigo JA, Van der Werf YD, Korf J and Krugers HJ . 1998 Neurosci Lett 241: 107–110
Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T and Sonenberg N . 1999 EMBO J 18: 270–279
Raught B and Gingras AC . 1999 Int J Bioch Cell Biol 31: 43–57
Rhee K, Bresnahan W, Kirai A, Kirai M and Thompson EA . 1995 Cancer Res 55: 4188–4195
Rosenwald IB, Chen JJ, Wan S, Savas L, London IM and Pullman J . 1999 Oncogene 18: 2507–2517
Rosenwald IB, Lazaris-Karatzas A, Sonenberg N and Schmidt EV . 1993 Mol Cell Biol 13: 7358–7363
Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N and London IM . 1995 J Biol Chem 270: 21176–21180
Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ and Schmidt EV . 1993 Proc Natl Acad Sci USA 90: 6175–6178
Rousseau D, Gingras AC, Pause A and Sonenberg N . 1996a Oncogene 13: 2415–2420
Rousseau D, Kaspar R, Rosenwald I, Gehrke L and Sonenberg N . 1996b Proc Natl Acad Sci USA 93: 1065–1070
Sauter ER, Nesbit M, Litwin S, Amdres KP, Klein-Szanto AJP, Cheffetz S and Herlyn M . 1999 Cancer Res 59: 4876–4881
Schuuring E, Verheoven E, van Tinteren H, Peterse JL, Nunnink B, Thunnissen FB, Devilee P, Cornelisse CJ, van de Vijver MJ, Mooi WJ, et al. 1992 Cancer Res 52: 5229–5234
Shantz LM and Pegg AE . 1994 Cancer Res 54: 2313–2316
Shantz LM, Hu R-H and Pegg AE . 1996 Cancer Res 56: 3265–3269
Sherr CJ and Roberts M . 1999 Genes Dev 13: 1501–1512
Sofer-Levi Y and Resnitzky D . 1996 Oncogene 13: 2431–2437
Sonenberg N . 1996 Translational Control Hershey JWB, Mathews MB and Sonenberg N eds. Cold Spring Harbor Laboratory Press Cold Spring Harbor pp 245–269
Sonenberg N and Gingras AC . 1998 Curr Opin Cell Biol 10: 268–275
Tam SW, Theodoras AM, Shay JW, Draetta GF and Pagano M . 1994 Oncogene 9: 2663–2674
Tan A, Levrey H, Dahm C, Polunovsky VA, Rubins J and Bitterman PB . 1999 Am J Respir Crit Care Med 159: 220–227
Thompson EB . 1998 Ann Rev Physiol 60: 575–600
Timsit S, Rivera S, Ouaghi P, Guischard F, Tremblay E, Ben-Ari Y and Khrestchatisky M . 1999 Eur J Neurosci 11: 263–278
Wang XT, Gorospe M, Huang Y and Holbrook NJ . 1997 Oncogene 9: 2663–2674
Warenius HM, Seabra LA and Maw P . 1996 Br J Cancer 67: 224–231
Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR and Cooper JA . 1999 Mol Cell Biol 19: 1871–1880
Zwijsen RML, Wientjens E, Klompmaker R, van der Sman J, Bernards R and Michalides RJ . 1997 Cell 88: 405–415
Acknowledgements
This work was supported by a grant from the NIH SCOR 2P50-HL50152. We are grateful to R Weinberg, P Leboulch and C Sherr for cell lines and constructs, and to I Rosenwald for valuable discussion. We thank J Murray and P Jung for technical assistance.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tan, A., Bitterman, P., Sonenberg, N. et al. Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1. Oncogene 19, 1437–1447 (2000). https://doi.org/10.1038/sj.onc.1203446
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203446
Keywords
This article is cited by
-
Targeting transcription factors in acute myeloid leukemia
International Journal of Hematology (2019)
-
Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL
Cell Death & Disease (2017)
-
Post-transcriptional regulation in cancer progression
Journal of Cell Communication and Signaling (2012)
-
mTOR, translation initiation and cancer
Oncogene (2006)
-
Parkin Modulates Gene Expression in Control and Ceramide-Treated PC12 Cells
Molecular Biology Reports (2006)