Function of Translationally Controlled Tumor Protein in Organ Growth: Lessons from Drosophila Studies

  • Kwang-Wook ChoiEmail author
  • Sung-Tae Hong
  • Thao Phuong Le
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 64)


Regulation of cell growth and proliferation is crucial for development and function of organs in all animals. Genetic defects in growth control can lead to developmental disorders and cancers. Translationally controlled tumor protein (TCTP) is a family of evolutionarily conserved proteins implicated in cancer. Recent studies have revealed multiple roles of TCTP in diverse cellular events, but TCTP functions in vivo are poorly understood in vertebrate systems. We have used Drosophila melanogaster, the fruit fly, as a model organism for genetic dissection of Tctp function. Our studies have shown that Tctp is essential for organ development by regulating growth signaling. Furthermore, it is required for genome stability by promoting DNA repair and chromatin remodeling in the nucleus. Thus, Tctp acts as a multifaceted cytosolic and nuclear factor for regulating organ growth and genome stability. In this chapter, we describe an overview of our findings on Tctp functions in Drosophila and discuss their implications in cancer.



We thank Kyungok Cho and Jean Jung for comments on the manuscript. This work was supported by NRF-2014K1A1A2042982, NRF-2017R1A2B3007516 (KWC), 2016R1D1A1B03932093 and 35B-2011-1-C00033 (STH) through the National Research Foundation of Korea funded by the Korean Ministry of Education Science & Technology.


  1. Acevedo SF, Tsigkari KK, Grammenoudi S, Skoulakis EM (2007) In vivo functional specificity and homeostasis of Drosophila 14-3-3 proteins. Genetics 177:239–253Google Scholar
  2. Aghazadeh Y, Papadopoulos V (2016) The role of the 14-3-3 protein family in health, disease, and drug development. Drug Discov Today 21:278–287CrossRefPubMedGoogle Scholar
  3. Aitken A, Baxter H, Dubois T, Clokie S, Mackie S, Mitchell K, Peden A, Zemlickova E (2002) Specificity of 14-3-3 isoform dimer interactions and phosphorylation. Biochem Soc Trans 30:351–360CrossRefPubMedGoogle Scholar
  4. Amson R, Kubiak JZ, Van Montagu M, Telerman A (2011) Could TCTP contribute to Armin Braun's paradigm of tumor reversion in plants? Cell Cycle 10:1CrossRefPubMedGoogle Scholar
  5. Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J et al (2012) Reciprocal repression between P53 and TCTP. Nat Med 18:91–99CrossRefGoogle Scholar
  6. Amson R, Pece S, Marine JC, Di Fiore PP, Telerman A (2013) TPT1/TCTP-regulated pathways in phenotypic reprogramming. Trends Cell Biol 23:37–46CrossRefPubMedGoogle Scholar
  7. Amzallag N, Passer BJ, Allanic D, Segura E, Thery C, Goud B, Amson R, Telerman A (2004) TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J Biol Chem 279:46104–46112CrossRefPubMedGoogle Scholar
  8. Bae SY, Kim HJ, Lee KJ, Lee K (2015) Translationally controlled tumor protein induces epithelial to mesenchymal transition and promotes cell migration, invasion and metastasis. Sci Rep 5:8061CrossRefPubMedPubMedCentralGoogle Scholar
  9. Baker NE (2007) Patterning signals and proliferation in Drosophila imaginal discs. Curr Opin Genet Dev 17:287–293CrossRefPubMedGoogle Scholar
  10. Bohm H, Benndorf R, Gaestel M, Gross B, Nurnberg P, Kraft R, Otto A, Bielka H (1989) The growth-related protein P23 of the Ehrlich ascites tumor: translational control, cloning and primary structure. Biochem Int 19:277–286PubMedGoogle Scholar
  11. Bommer UA, Thiele BJ (2004) The translationally controlled tumour protein (TCTP). Int J Biochem Cell Biol 36:379–385CrossRefPubMedGoogle Scholar
  12. Bonnet C, Perret E, Dumont X, Picard A, Caput D, Lenaers G (2000) Identification and transcription control of fission yeast genes repressed by an ammonium starvation growth arrest. Yeast 16:23–33CrossRefPubMedGoogle Scholar
  13. Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415PubMedGoogle Scholar
  14. Brioudes F, Thierry AM, Chambrier P, Mollereau B, Bendahmane M (2010) Translationally controlled tumor protein is a conserved mitotic growth integrator in animals and plants. Proc Natl Acad Sci U S A 107:16384–16389CrossRefPubMedPubMedCentralGoogle Scholar
  15. Burton J, Roberts D, Montaldi M, Novick P, De Camilli P (1993) A mammalian guanine-nucleotide-releasing protein enhances function of yeast secretory protein Sec4. Nature 361:464–467CrossRefPubMedGoogle Scholar
  16. Cheng X, Li J, Deng J, Li Z, Meng S, Wang H (2012) Translationally controlled tumor protein (TCTP) downregulates Oct4 expression in mouse pluripotent cells. BMB Rep 45:20–25CrossRefPubMedGoogle Scholar
  17. Chitpatima ST, Makrides S, Bandyopadhyay R, Brawerman G (1988) Nucleotide sequence of a major messenger RNA for a 21 kilodalton polypeptide that is under translational control in mouse tumor cells. Nucleic Acids Res 16:2350CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chung S, Kim M, Choi W, Chung J, Lee K (2000) Expression of translationally controlled tumor protein mRNA in human colon cancer. Cancer Lett 156:185–190CrossRefPubMedGoogle Scholar
  19. Cohen SM, Di Nardo S (1993) Wingless: from embryo to adult. Trends Genet 9:189–192CrossRefPubMedGoogle Scholar
  20. Datar SA, Galloni M, de la Cruz A, Marti M, Edgar BA, Frei C (2006) Mammalian cyclin D1/Cdk4 complexes induce cell growth in Drosophila. Cell Cycle 5:647–652Google Scholar
  21. Dong J, Pan D (2004) Tsc2 is not a critical target of Akt during normal Drosophila development. Genes Dev 18:2479–2484Google Scholar
  22. Dong X, Yang B, Li Y, Zhong C, Ding J (2009) Molecular basis of the acceleration of the GDP-GTP exchange of human ras homolog enriched in brain by human translationally controlled tumor protein. J Biol Chem 284:23754–23764CrossRefPubMedPubMedCentralGoogle Scholar
  23. Fonseca BD, Smith EM, Lee VH, MacKintosh C, Proud CG (2007) PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 282:24514–24524CrossRefPubMedGoogle Scholar
  24. Gachet Y, Tournier S, Lee M, Lazaris-Karatzas A, Poulton T, Bommer UA (1999) The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle. J Cell Sci 112(Pt 8):1257–1271PubMedGoogle Scholar
  25. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466CrossRefPubMedGoogle Scholar
  26. Gong X, Yan L, Gu H, Mu Y, Tong G, Zhang G (2014) 14-3-3epsilon functions as an oncogene in SGC7901 gastric cancer cells through involvement of cyclin E and p27kip1. Mol Med Rep 10:3145–3150CrossRefPubMedGoogle Scholar
  27. Guillaume E, Pineau C, Evrard B, Dupaix A, Moertz E, Sanchez JC, Hochstrasser DF, Jegou B (2001) Cellular distribution of translationally controlled tumor protein in rat and human testes. Proteomics 1:880–889CrossRefPubMedGoogle Scholar
  28. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, Ferrari S (1998) Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 273:14424–14429CrossRefPubMedGoogle Scholar
  29. Hong ST, Choi KW (2013) TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster. Nat Commun 4:2986CrossRefPubMedGoogle Scholar
  30. Hong ST, Choi KW (2016) Antagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences. Nat Commun 7:12988CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW (2007) Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 445:785–788CrossRefPubMedGoogle Scholar
  32. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657CrossRefPubMedGoogle Scholar
  33. Jeon HJ, You SY, Park YS, Chang JW, Kim JS, Oh JS (2016) TCTP regulates spindle microtubule dynamics by stabilizing polar microtubules during mouse oocyte meiosis. Biochim Biophys Acta 1863:630–637CrossRefPubMedGoogle Scholar
  34. Jewell JL, Russell RC, Guan KL (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14:133–139CrossRefPubMedPubMedCentralGoogle Scholar
  35. Jung J, Kim HY, Kim M, Sohn K, Kim M, Lee K (2011) Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src. Oncogene 30:2264–2274CrossRefPubMedGoogle Scholar
  36. Kim M, Jung Y, Lee K, Kim C (2000) Identification of the calcium binding sites in translationally controlled tumor protein. Arch Pharm Res 23:633–636CrossRefPubMedGoogle Scholar
  37. Kim MJ, Kwon JS, Suh SH, Suh JK, Jung J, Lee SN, Kim YH, Cho MC, Oh GT, Lee K (2008) Transgenic overexpression of translationally controlled tumor protein induces systemic hypertension via repression of Na+,K+-ATPase. J Mol Cell Cardiol 44:151–159Google Scholar
  38. Kim M, Min HJ, Won HY, Park H, Lee JC, Park HW, Chung J, Hwang ES, Lee K (2009) Dimerization of translationally controlled tumor protein is essential for its cytokine-like activity. PLoS One 4:e6464CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kloc M, Tejpal N, Sidhu J, Ganachari M, Flores-Villanueva P, Jennings NB, Sood AK, Kubiak JZ, Ghobrial RM (2012) Inverse relationship between TCTP/RhoA and p53/cyclin a/actin expression in ovarian cancer cells. Folia Histochem Cytobiol 50:358–367CrossRefPubMedPubMedCentralGoogle Scholar
  40. Koziol MJ, Garrett N, Gurdon JB (2007) Tpt1 activates transcription of oct4 and nanog in transplanted somatic nuclei. Curr Biol 17:801–807CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kuo LJ, Yang LX (2008) Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo 22:305–309PubMedGoogle Scholar
  42. Laplante M, Sabatini DM (2012a) mTOR signaling. Cold Spring Harb Perspect Biol 4Google Scholar
  43. Laplante M, Sabatini DM (2012b) mTOR signaling in growth control and disease. Cell 149:274–293CrossRefPubMedPubMedCentralGoogle Scholar
  44. Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K, Guo D, Eickbush TH, Li WX (2012) Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 8:e1002473CrossRefPubMedPubMedCentralGoogle Scholar
  45. Le TP, Vuong LT, Kim AR, Hsu YC, Choi KW (2016) 14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila. Nat Commun 7:11501Google Scholar
  46. Lee T, Luo L (2001) Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci 24:251–254Google Scholar
  47. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733CrossRefPubMedGoogle Scholar
  48. Li Y, Inoki K, Yeung R, Guan KL (2002) Regulation of TSC2 by 14-3-3 binding. J Biol Chem 277:44593–44596CrossRefPubMedGoogle Scholar
  49. Liu H, Peng HW, Cheng YS, Yuan HS, Yang-Yen HF (2005) Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP. Mol Cell Biol 25:3117–3126CrossRefPubMedPubMedCentralGoogle Scholar
  50. MacDonald SM, Rafnar T, Langdon J, Lichtenstein LM (1995) Molecular identification of an IgE-dependent histamine-releasing factor. Science 269:688–690CrossRefPubMedGoogle Scholar
  51. MacDonald SM, Bhisutthibhan J, Shapiro TA, Rogerson SJ, Taylor TE, Tembo M, Langdon JM, Meshnick SR (2001) Immune mimicry in malaria: Plasmodium falciparum secretes a functional histamine-releasing factor homolog in vitro and in vivo. Proc Natl Acad Sci U S A 98:10829–10832CrossRefPubMedPubMedCentralGoogle Scholar
  52. Miron M, Verdu J, Lachance PE, Birnbaum MJ, Lasko PF, Sonenberg N (2001) The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Nat Cell Biol 3:596–601Google Scholar
  53. Morrison DK (2009) The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol 19:16–23CrossRefPubMedGoogle Scholar
  54. Moya M, Roberts D, Novick P (1993) DSS4-1 is a dominant suppressor of sec4-8 that encodes a nucleotide exchange protein that aids Sec4p function. Nature 361:460–463CrossRefPubMedGoogle Scholar
  55. Nielsen HV, Johnsen AH, Sanchez JC, Hochstrasser DF, Schiotz PO (1998) Identification of a basophil leukocyte interleukin-3-regulated protein that is identical to IgE-dependent histamine-releasing factor. Allergy 53:642–652CrossRefPubMedGoogle Scholar
  56. Niforou KM, Anagnostopoulos AK, Vougas K, Kittas C, Gorgoulis VG, Tsangaris GT (2008) The proteome profile of the human osteosarcoma U2OS cell line. Cancer Genomics Proteomics 5:63–78PubMedGoogle Scholar
  57. Norbeck J, Blomberg A (1997) Two-dimensional electrophoretic separation of yeast proteins using a non-linear wide range (pH 3-10) immobilized pH gradient in the first dimension; reproducibility and evidence for isoelectric focusing of alkaline (pI > 7) proteins. Yeast 13:1519–1534CrossRefPubMedGoogle Scholar
  58. Obsilova V, Silhan J, Boura E, Teisinger J, Obsil T (2008) 14-3-3 proteins: a family of versatile molecular regulators. Physiol Res 57(Suppl 3):S11–S21PubMedGoogle Scholar
  59. Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E (2000) Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev 14:2689–2694CrossRefPubMedPubMedCentralGoogle Scholar
  60. Pallares-Cartes C, Cakan-Akdogan G, Teleman AA (2012) Tissue-specific coupling between insulin/IGF and TORC1 signaling via PRAS40 in drosophila. Dev Cell 22:172–182CrossRefPubMedGoogle Scholar
  61. Peng JC, Karpen GH (2007) H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat Cell Biol 9:25–35CrossRefPubMedGoogle Scholar
  62. Peng JC, Karpen GH (2009) Heterochromatic genome stability requires regulators of histone H3 K9 methylation. PLoS Genet 5:e1000435CrossRefPubMedPubMedCentralGoogle Scholar
  63. Predic J, Soskic V, Bradley D, Godovac-Zimmermann J (2002) Monitoring of gene expression by functional proteomics: response of human lung fibroblast cells to stimulation by endothelin-1. Biochemistry 41:1070–1078CrossRefPubMedGoogle Scholar
  64. Rehmann H, Bruning M, Berghaus C, Schwarten M, Kohler K, Stocker H, Stoll R, Zwartkruis FJ, Wittinghofer A (2008) Biochemical characterisation of TCTP questions its function as a guanine nucleotide exchange factor for Rheb. FEBS Lett 582:3005–3010CrossRefPubMedGoogle Scholar
  65. Rho SB, Lee JH, Park MS, Byun HJ, Kang S, Seo SS, Kim JY, Park SY (2011) Anti-apoptotic protein TCTP controls the stability of the tumor suppressor p53. FEBS Lett 585:29–35CrossRefPubMedGoogle Scholar
  66. Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM (1995) Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 270:21176–21180CrossRefPubMedGoogle Scholar
  67. Sanchez JC, Schaller D, Ravier F, Golaz O, Jaccoud S, Belet M, Wilkins MR, James R, Deshusses J, Hochstrasser D (1997) Translationally controlled tumor protein: a protein identified in several nontumoral cells including erythrocytes. Electrophoresis 18:150–155CrossRefPubMedGoogle Scholar
  68. Saucedo LJ, Gao XS, Chiarelli DA, Li L, Pan D, Edgar BA (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5:566–571CrossRefPubMedGoogle Scholar
  69. Shi S, Larson K, Guo D, Lim SJ, Dutta P, Yan SJ, Li WX (2008) Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol 10:489–496CrossRefPubMedPubMedCentralGoogle Scholar
  70. Singh A, Lim J, Choi KW (2005) Dorsoventral boundary for organizing growth and planar polarity in the Drosophila eye. In: Mlodzik M (ed) Advances in developmental biology: planar cell polarization during development. Elsevier, Amsterdam, p 59, 172pGoogle Scholar
  71. Skoulakis EM, Davis RL (1996) Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein. Neuron 17:931–944CrossRefPubMedGoogle Scholar
  72. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5:559–566CrossRefPubMedGoogle Scholar
  73. Susini L, Besse S, Duflaut D, Lespagnol A, Beekman C, Fiucci G, Atkinson AR, Busso D, Poussin P, Marine JC et al (2008) TCTP protects from apoptotic cell death by antagonizing bax function. Cell Death Differ 15:1211–1220CrossRefPubMedGoogle Scholar
  74. Telerman A, Amson R (2009) The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 9:206–216CrossRefPubMedGoogle Scholar
  75. Thaw P, Baxter NJ, Hounslow AM, Price C, Waltho JP, Craven CJ (2001) Structure of TCTP reveals unexpected relationship with guanine nucleotide-free chaperones. Nat Struct Biol 8:701–704CrossRefPubMedGoogle Scholar
  76. Thebault S, Agez M, Chi X, Stojko J, Cura V, Telerman SB, Maillet L, Gautier F, Billas-Massobrio I, Birck C et al (2016) TCTP contains a BH3-like domain, which instead of inhibiting, activates Bcl-xL. Sci Rep 6:19725CrossRefPubMedPubMedCentralGoogle Scholar
  77. Tuynder M, Susini L, Prieur S, Besse S, Fiucci G, Amson R, Telerman A (2002) Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proc Natl Acad Sci U S A 99:14976–14981CrossRefPubMedPubMedCentralGoogle Scholar
  78. Tuynder M, Fiucci G, Prieur S, Lespagnol A, Geant A, Beaucourt S, Duflaut D, Besse S, Susini L, Cavarelli J et al (2004) Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci U S A 101:15364–15369CrossRefPubMedPubMedCentralGoogle Scholar
  79. Wang X, Fonseca BD, Tang H, Liu R, Elia A, Clemens MJ, Bommer UA, Proud CG (2008) Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J Biol Chem 283:30482–30492CrossRefPubMedPubMedCentralGoogle Scholar
  80. Xu T, Rubin GM (1993) Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117:1223–1237PubMedGoogle Scholar
  81. Yaffe MB (2002) How do 14-3-3 proteins work?-- gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett 513:53–57CrossRefPubMedGoogle Scholar
  82. Zhang H, Stallock JP, Ng JC, Reinhard C, Neufeld TP (2000) Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev 14:2712–2724Google Scholar
  83. Zhang Y, Gao XS, Saucedo LJ, Ru BG, Edgar BA, Pan DJ (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5:578–581CrossRefPubMedGoogle Scholar
  84. Zhang J, de Toledo SM, Pandey BN, Guo G, Pain D, Li H, Azzam EI (2012) Role of the translationally controlled tumor protein in DNA damage sensing and repair. Proc Natl Acad Sci U S A 109:E926–E933CrossRefPubMedPubMedCentralGoogle Scholar
  85. Zhao J, Meyerkord CL, Du Y, Khuri FR, Fu H (2011) 14-3-3 proteins as potential therapeutic targets. Semin Cell Dev Biol 22:705–712CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  • Kwang-Wook Choi
    • 1
    Email author
  • Sung-Tae Hong
    • 2
  • Thao Phuong Le
    • 1
  1. 1.Department of Biological SciencesKorea Advanced Institute of Science and TechnologyDaejeonSouth Korea
  2. 2.Department of Anatomy & Cell Biology, College of MedicineChungnam National UniversityDaejeonSouth Korea

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