The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation
The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein.
TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants.
Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole-body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals.
Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such as invasion and metastasis. Hence, high TCTP levels in tumour tissues are often associated with a poor patient outcome. Due to its multiple roles in cancer progression, TCTP has been proposed as a potential target for the development of new anti-cancer strategies in recent pilot studies. Apart from its role in cancer, TCTP dysregulation has been reported to contribute to certain processes in the development of diabetes, as well as in diseases associated with the cardiovascular system.
Since cellular TCTP levels are highly regulated, e.g. in response to cell stress or to growth signalling, and because deregulation of this protein contributes to many disease processes, a detailed understanding of regulatory processes that impinge on TCTP levels is required. The last section of this chapter summarises our current knowledge on the mechanisms that may be involved in the regulation of TCTP levels. Essentially, expression of the TPT1 gene is regulated at both the transcriptional and the translational level, the latter being particularly advantageous when a rapid adjustment of cellular TCTP levels is required, for example in cell stress responses. Other regulatory mechanisms, such as protein stability regulation, may also contribute to the regulation of overall TCTP levels.
Work in my laboratory was supported by project grants from The Wellcome Trust (UK), by a Short-Term Fellowship from the Human Frontier Science Program (Strasbourg) and by small grants from the Cancer Prevention Research Trust (London, UK). I received small grants from the Illawarra Health and Medical Research Institute and from the Graduate School of Medicine, University of Wollongong, NSW, Australia. I wish to thank all friends and colleagues, who contributed to our work.
- Arcuri F, Papa S, Carducci A, Romagnoli R, Liberatori S, Riparbelli MG, Sanchez J-C, Tosi P, del Vecchio MT (2004) Translationally controlled tumor protein (TCTP) in the human prostate and prostate cancer cells: expression, distribution, and calcium binding activity. Prostate 60(2):130–140PubMedCrossRefGoogle Scholar
- Arcuri F, Papa S, Meini A, Carducci A, Romagnoli R, Bianchi L, Riparbelli MG, Sanchez J-C, Palmi M, Tosi P et al (2005) The translationally controlled tumor protein is a novel calcium binding protein of the human placenta and regulates calcium handling in trophoblast cells. Biol Reprod 73(4):745–751PubMedCrossRefGoogle Scholar
- Bhisutthibhan J, Meshnick SR (2001) Immunoprecipitation of [(3)H]dihydroartemisinin translationally controlled tumor protein (TCTP) adducts from Plasmodium falciparum-infected erythrocytes by using anti-TCTP antibodies. Antimicrob Agents Chemother 45(8):2397–2399PubMedPubMedCentralCrossRefGoogle Scholar
- Bommer UA, Borovjagin AV, Greagg MA, Jeffrey IW, Russell P, Laing KG, Lee M, Clemens MJ (2002) The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR. RNA 8(4):478–496PubMedPubMedCentralCrossRefGoogle Scholar
- Bommer UA, Vine KL, Puri P, Engel M, Belfiore L, Fildes K, Batterham M, Lochhead A, Aghmesheh M (2017) Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin. Cell Commun Signal 15(1):9PubMedPubMedCentralCrossRefGoogle Scholar
- Budde IK, Lopuhaa CE, de Heer PG, Langdon JM, MacDonald SM, van der Zee JS, Aalberse RC (2002) Lack of correlation between bronchial late allergic reaction to Dermatophagoides pteronyssinus and in vitro immunoglobulin E reactivity to histamine-releasing factor derived from mononuclear cells. Ann Allergy Asthma Immunol 89(6):606–612PubMedCrossRefGoogle Scholar
- Calderon-Perez B, Xoconostle-Cazares B, Lira-Carmona R, Hernandez-Rivas R, Ortega-Lopez J, Ruiz-Medrano R (2014) The Plasmodium falciparum translationally controlled tumor protein (TCTP) is incorporated more efficiently into B cells than its human homologue. PLoS One 9(1):e85514PubMedPubMedCentralCrossRefGoogle Scholar
- Cans C, Passer BJ, Shalak V, Nancy-Portebois V, Crible V, Amzallag N, Allanic D, Tufino R, Argentini M, Moras D et al (2003) Translationally controlled tumor protein acts as a guanine nucleotide dissociation inhibitor on the translation elongation factor eEF1A. Proc Natl Acad Sci U S A 100(24):13892–13897PubMedPubMedCentralCrossRefGoogle Scholar
- Chattopadhyay A, Pinkaew D, Doan HQ, Jacob RB, Verma SK, Friedman H, Peterson AC, Kuyumcu-Martinez MN, McDougal OM, Fujise K (2016) Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice. Sci Rep 6:18701PubMedPubMedCentralCrossRefGoogle Scholar
- Chen SH, Wu P-S, Chou C-H, Yan Y-T, Liu H, Weng S-Y, Yang-Yen H-F (2007a) A knockout mouse approach reveals that TCTP functions as an essential factor for cell proliferation and survival in a tissue- or cell type-specific manner. Mol Biol Cell 18(7):2525–2532Google Scholar
- Chen Z, Zhang H, Yang H, Huang X, Zhang X, Zhang P (2007b) The expression of AmphiTCTP, a TCTP orthologous gene in amphioxus related to the development of notochord and somites. Comp Biochem Physiol B Biochem Mol Biol 147(3):460–465Google Scholar
- Chen K, Chen S, Huang C, Cheng H, Zhou R (2013a) TCTP increases stability of hypoxia-inducible factor 1alpha by interaction with and degradation of the tumour suppressor VHL. Biol Cell 105(5):208–218Google Scholar
- Chen W, Wang H, Tao S, Zheng Y, Wu W, Lian F, Jaramillo M, Fang D, Zhang DD (2013b) Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival. Cell Cycle 12(14):2321–2328Google Scholar
- Chen K, Huang C, Yuan J, Cheng H, Zhou R (2014a) Long-term artificial selection reveals a role of TCTP in autophagy in mammalian cells. Mol Biol Evol 31(8):2194–2211Google Scholar
- Chen Y, Chen X, Wang H, Bao Y, Zhang W (2014b) Examination of the leaf proteome during flooding stress and the induction of programmed cell death in maize. Proteome Sci 12:33Google Scholar
- Chu ZH, Liu L, Zheng CX, Lai W, Li SF, Wu H, Zeng YJ, Zhao HY, Guan YF (2011) Proteomic analysis identifies translationally controlled tumor protein as a mediator of phosphatase of regenerating liver-3-promoted proliferation, migration and invasion in human colon cancer cells. Chin Med J 124(22):3778–3785PubMedGoogle Scholar
- de Carvalho M, Acencio ML, AVN L, de Araujo LM, de Lara Campos Arcuri M, do Nascimento LC, Maia IG (2017) Impacts of the overexpression of a tomato translationally controlled tumor protein (TCTP) in tobacco revealed by phenotypic and transcriptomic analysis. Plant Cell Rep 36(6):887–900PubMedCrossRefGoogle Scholar
- Diraison F, Hayward K, Sanders KL, Brozzi F, Lajus S, Hancock J, Francis JE, Ainscow E, Bommer UA, Molnar E et al (2011) Translationally controlled tumour protein (TCTP) is a novel glucose-regulated protein that is important for survival of pancreatic beta cells. Diabetologia 54(2):368–379PubMedCrossRefGoogle Scholar
- Feng Y, Liu D, Yao H, Wang J (2007a) Solution structure and mapping of a very weak calcium-binding site of human translationally controlled tumor protein by NMR. Arch Biochem Biophys 467(1):48–57Google Scholar
- Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ (2007b) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67(7):3043–3053Google Scholar
- Gnanasekar M, Rao KVN, Chen L, Narayanan RB, Geetha M, Scott AL, Ramaswamy K, Kaliraj P (2002) Molecular characterization of a calcium binding translationally controlled tumor protein homologue from the filarial parasites Brugia malayi and Wuchereria bancrofti. Mol Biochem Parasitol 121(1):107–118PubMedCrossRefGoogle Scholar
- Gremski LH, Trevisan-Silva D, Ferrer VP, Matsubara FH, Meissner GO, Wille AC, Vuitika L, Dias-Lopes C, Ullah A, de Moraes FR et al (2014) Recent advances in the understanding of brown spider venoms: from the biology of spiders to the molecular mechanisms of toxins. Toxicon 83:91–120PubMedCrossRefGoogle Scholar
- He S, Huang Y, Wang Y, Tang J, Song Y, Yu X, Ma J, Wang S, Yin H, Li Q et al (2015) Histamine-releasing factor/translationally controlled tumor protein plays a role in induced cell adhesion, apoptosis resistance and chemoresistance in non-Hodgkin lymphomas. Leuk Lymphoma 56(7):2153–2161PubMedCrossRefGoogle Scholar
- Kim M-J, Kwon J-S, Suh SH, Suh J-K, Jung J, Lee S-N, Kim Y-H, Cho M-C, Oh GT, Lee K (2008a) Transgenic overexpression of translationally controlled tumor protein induces systemichypertension via repression of Na+, K+-ATPase. J Mol Cell Cardiol 44(1):151–159Google Scholar
- Kim JE, Koo KH, Kim YH, Sohn J, Park YG (2008b) Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 40(6):709–720Google Scholar
- Kim YM, Han YJ, Hwang OJ, Lee SS, Shin AY, Kim SY, Kim JI (2012a) Overexpression of Arabidopsis translationally controlled tumor protein gene AtTCTP enhances drought tolerance with rapid ABA-induced stomatal closure. Mol Cells 33(6):617–626Google Scholar
- Kim DK, Nam BY, Li JJ, Park JT, Lee SH, Kim DH, Kim JY, Kang HY, Han SH, Yoo TH et al (2012b) Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes. Diabetologia 55(4):1205–1217Google Scholar
- Kobayashi D, Hirayama M, Komohara Y, Mizuguchi S, Wilson Morifuji M, Ihn H, Takeya M, Kuramochi A, Araki N (2014) Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1 (NF1)-associated tumors. J Biol Chem 289(38):26314–26326PubMedPubMedCentralCrossRefGoogle Scholar
- Langdon JM, Vonakis BM, MacDonald SM (2004) Identification of the interaction between the human recombinant histamine releasing factor/translationally controlled tumor protein and elongation factor-1 delta (also known as eElongation factor-1B beta). Biochim Biophys Acta 1688(3):232–236PubMedCrossRefGoogle Scholar
- Lavoie JR, Ormiston ML, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW et al (2014) Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation 129(21):2125–2135PubMedCrossRefGoogle Scholar
- 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(19):10829–10832PubMedPubMedCentralCrossRefGoogle Scholar
- Meyvis Y, Houthoofd W, Visser A, Borgonie G, Gevaert K, Vercruysse J, Claerebout E, Geldhof P (2009) Analysis of the translationally controlled tumour protein in the nematodes Ostertagia ostertagi and Caenorhabditis elegans suggests a pivotal role in egg production. Int J Parasitol 39(11):1205–1213PubMedCrossRefGoogle Scholar
- Rid R, Simon-Nobbe B, Langdon J, Holler C, Wally V, Poll V, Ebner C, Hemmer W, Hawranek T, Lang R et al (2008) Cladosporium herbarum translationally controlled tumor protein (TCTP) is an IgE-binding antigen and is associated with disease severity. Mol Immunol 45(2):406–418PubMedCrossRefGoogle Scholar
- Rid R, Onder K, Trost A, Bauer J, Hintner H, Ritter M, Jakab M, Costa I, Reischl W, Richter K et al (2010) H2O2-dependent translocation of TCTP into the nucleus enables its interaction with VDR in human keratinocytes: TCTP as a further module in calcitriol signalling. J Steroid Biochem Mol Biol 118(1–2):29–40PubMedCrossRefGoogle Scholar
- Rinnerthaler M, Jarolim S, Heeren G, Palle E, Perju S, Klinger H, Bogengruber E, Madeo F, Braun RJ, Breitenbach-Koller L et al (2006) MMI1 (YKL056c, TMA19), the yeast orthologue of the translationally controlled tumor protein (TCTP) has apoptotic functions and interacts with both microtubules and mitochondria. Biochim Biophys Acta 1757(5–6):631–638PubMedCrossRefGoogle Scholar
- Rinnerthaler M, Lejskova R, Grousl T, Stradalova V, Heeren G, Richter K, Breitenbach-Koller L, Malinsky J, Hasek J, Breitenbach M (2013) Mmi1, the yeast homologue of mammalian TCTP, associates with stress granules in heat-shocked cells and modulates proteasome activity. PLoS One 8(10):e77791PubMedPubMedCentralCrossRefGoogle Scholar
- Sade YB, Boia-Ferreira M, Gremski LH, da Silveira RB, Gremski W, Senff-Ribeiro A, Chaim OM, Veiga SS (2012) Molecular cloning, heterologous expression and functional characterization of a novel translationally-controlled tumor protein (TCTP) family member from Loxosceles intermedia (brown spider) venom. Int J Biochem Cell Biol 44(1):170–177PubMedCrossRefGoogle Scholar
- Seo J, Maeng J, Kim HJ (2016) Translationally controlled tumor protein stimulates dopamine release from PC12 cells via Ca2+-independent phospholipase A(2) pathways. Int J Mol Sci 17(10)Google Scholar
- Sinha P, Kohl S, Fischer J, Hutter G, Kern M, Kottgen E, Dietel M, Lage H, Schnolzer M, Schadendorf D (2000) Identification of novel proteins associated with the development of chemoresistance in malignant melanoma using two-dimensional electrophoresis. Electrophoresis 21(14):3048–3057PubMedCrossRefGoogle Scholar
- Tao JJ, Cao YR, Chen HW, Wei W, Li QT, Ma B, Zhang WK, Chen SY, Zhang JS (2015) Tobacco translationally controlled tumor protein interacts with ethylene receptor tobacco histidine kinase1 and enhances plant growth through promotion of cell proliferation. Plant Physiol 169(1):96–114PubMedPubMedCentralCrossRefGoogle Scholar
- Vonakis BM, Gibbons S Jr, Sora R, Langdon JM, MacDonald SM (2001) Src homology 2 domain-containing inositol 5’ phosphatase is negatively associated with histamine release to human recombinant histamine-releasing factor in human basophils. J Allergy Clin Immunol 108(5):822–831PubMedCrossRefGoogle Scholar
- Vonakis BM, Macglashan DW Jr, Vilarino N, Langdon JM, Scott RS, MacDonald SM (2008) Distinct characteristics of signal transduction events by histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced priming and activation of human basophils. Blood 111(4):1789–1796PubMedPubMedCentralCrossRefGoogle Scholar