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The International Journal of Biochemistry & Cell Biology 36 (2004) 379385

Molecules in focus

The translationally controlled tumour protein (TCTP)


Ulrich-Axel Bommer a, , Bernd-Joachim Thiele b,1
a

Department of Basic Medical Sciences, St. Georges Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK b Institut fr Physiologie der Charite, Humboldt-Universitt, Tucholskystr. 2, D-10117 Berlin, Germany Received 17 April 2003; received in revised form 19 May 2003; accepted 19 May 2003

Abstract The translationally controlled tumour protein (TCTP) is a highly conserved protein that is widely expressed in all eukaryotic organisms. Based on its sequence, TCTP was listed as a separate protein family in protein databases but the recent elucidation of the solution structure of the ssion yeast orthologue places it close to a family of small chaperone proteins. The molecular functions determined so far, Ca2+ - and microtubule-binding, have been mapped to an -helical region of the molecule. TCTP expression is highly regulated both at the transcriptional and translational level and by a wide range of extracellular signals. TCTP has been implicated in important cellular processes, such as cell growth, cell cycle progression, malignant transformation and in the protection of cells against various stress conditions and apoptosis. In addition, an extracellular, cytokine-like function has been established for TCTP, and the protein has been implicated in various medically relevant processes. 2003 Elsevier Ltd. All rights reserved.
Keywords: Translationally controlled tumour protein (TCTP); TPT1 gene; Histamine releasing factor (HRF); Fortilin

1. Introduction The translationally controlled tumour protein (TCTP) was discovered about 20 years ago by three groups interested in translationally regulated genes. They named this protein P21, Q23 and P23, respectively (reviewed in Gachet et al. (1999)). The cDNA sequences of the mouse (Chitpatima, Makrides, Bandyopadhyay, & Brawerman, 1988) and the human protein (Gross, Gaestel, Boehm, & Bielka, 1989) were published in the late eighties. At this time the name translationally controlled tumour protein was coined (Gross et al., 1989), based on the fact that the
Corresponding author. Tel.: +44-20-8725-5754; fax: +44-20-8725-2992. E-mail addresses: u.bommer@sghms.ac.uk (U.-A. Bommer), bernd.thiele@charite.de (B.-J. Thiele). 1 Tel.: +49-30-4505-28184; fax: +49-30-4505-28972.

cDNA was cloned from a human tumour and on the observation that TCTP is regulated at the translational level. Elucidation of the primary sequence did not reveal any similarity with other protein families. Only the recent determination of the solution structure of the ssion yeast protein (Thaw et al., 2001) indicated similarity with a small chaperone family. Recently TCTP has attracted the attention of an increasing number of researchers interested in various biologically and medically relevant processes. This is largely due to the fact that TCTP levels are highly regulated in response to a wide range of extracellular stimuli. A series of recent reports highlighted the importance of TCTP for cell cycle progression and malignant transformation. In addition, TCTP was shown to display an extracellular function as a histamine release factor and to have anti-apoptotic activity. These ndings led the authors to suggest yet other names for this protein, such as histamine releasing factor (HRF)

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(MacDonald, Rafnar, Langdon, & Lichtenstein, 1995) and fortilin (Li, Zhang, & Fujise, 2001). However, each of these designations emphasises only a particular function of this interesting protein and does not fully appreciate its wide-ranging biological importance. 2. Structure 2.1. Protein structure and conservation Sequence alignment of TCTP sequences from more than 30 different species reveals a high degree of conservation over a long period of evolution. In Fig. 1A, we aligned TCTP sequences from ve species representing one kingdom each. Nine of the approximately 170 residues are completely conserved and six additional ones are only mismatched in one sequence, making up a total of nearly 9% absolutely conserved amino acids. The invariant residues are largely clustered on one side of the -stranded core domain (Fig. 1B), indicating that this side is important for molecular interactions. The fold of this domain displays signicant similarity to that of the Mss4 and Dss4 proteins, two small chaperones reported to bind to the nucleotide-free form of Rab proteins (Thaw et al., 2001). TCTP is therefore now grouped in one protein family together with Mss4/Dss4. The other major domains, the exible loop and the helical domain (Fig. 1B), are specic for TCTP. The middle of the loop contains a highly conserved area, listed in the prosite database as TCTP signature 1. The only molecular functions of the TCTP protein mapped so far are the tubulin-binding region (Gachet et al., 1999) and the Ca2+ -binding area (Kim, Jung, Lee, & Kim, 2000). Both coincide with the helical domain, which also represents the most basic part of the molecule (Gachet et al., 1999; Thaw et al., 2001). 2.2. Gene structure and pseudogenes The genomic structures of four mammalian TPT1 genes are currently available, from humans (NT009910), mouse (NT039606), rat (NW043879) and rabbit (Z46805). All four genes are of identical intron/exon organisation with ve introns and six exons. The boundaries of exons 15 are indicated in Fig. 1A in relation to the amino acid sequence.

Exon 6 comprises the 3 -UTR of the mRNA. The chromosomal localisation has been determined for the human, rat and mouse genes. The TPT1-gene contains a promoter with a canonical TATA-box and several promoter elements, which are well-conserved in mammals. In reporter gene assays, this region exhibits a strong promoter activity comparable to viral promoters (Thiele, Berger, Lenzner, Kuhn, & Thiele, 1998). Mammalian genomes contain substantial numbers of intron-less, processed TPT1 pseudogenes. A genomic BLAST search detects 15 pseudogenes in humans, 18 in rat and 13 in mouse. All these represent cDNA-like, processed pseudogenes with a high degree of conservation. In rabbit, the number of TPT1 pseudogenes was estimated to be in the range of about 1015 (Thiele, Berger, Skalweit, & Thiele, 2000). 2.3. Features of TCTP mRNAs The TPT1 gene is transcribed into two mRNAs, which differ only in the length of their 3 -UTRs and are generated by the use of two alternative polyadenylation signals. All mammalian tissues investigated so far express both types of TCTP mRNAs, however in different ratios, the shorter mRNA usually being more abundant (Thiele et al., 2000). TCTP mRNAs display the following features typical for translationally controlled mRNAs: (1) The 5 -UTR starts with a 5 -terminal oligopyrimidine tract (5 -TOP), characteristic for a certain group of translationally controlled mRNAs, such as ribosomal protein mRNAs. (2) The 5 -UTR is CG-rich (nearly 80%), which is indicative of a high degree of secondary structure. The mouse TCTP mRNA has indeed been shown to be a highly structured RNA that is able to bind to and activate the dsRNA-dependent protein kinase PKR (Bommer et al., 2002). (3) The 3 -UTR harbours AU-rich regions and AUUUA elements, but these do not match the classical mRNA instability elements. 3. Synthesis and degradation 3.1. Expression TCTP is ubiquitously expressed in all eukaryotic organisms and in more than 500 tissues and cell types investigated so far. However expression levels vary

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Fig. 1. Sequence conservation, 3D structure and functional mapping of the TCTP protein. (A) TCTP sequences of the following species were aligned: ssion yeast (S. pombe; Q10344), pea (P. sativum; P50906), a nematode (C. elegans; Q93573), the fruit y (Drosophila; Q9VGS2) and mouse (P14701). Numbering is for the S. pombe sequence. Invariant residues are labelled in red, residues conserved in all but one of 30 TCTP sequences are highlighted in pink. Exon boundaries are indicated by boxes at the top. Secondary structure elements of the ssion yeast protein (Thaw et al., 2001) are represented as follows, -strands: yellow arrows, helices: orange bars, coiled regions: grey line. The microtubule-binding region (Gachet et al., 1999) and the Ca2+ -binding region (Kim et al., 2000) are indicated by a blue bar and a green bar, respectively. Residues of the mouse sequence that match amino acids within part of the tubulin-binding region of human MAP-1B (Gachet et al., 1999) are highlighted in blue. Serine residues in the mouse sequence that are phosphorylated by the mitotic kinase Plk (Yarm, 2002) are labelled in green. Note that these serines are only conserved in mammalians. TCTP signatures listed in the prosite database are shown in rose. (B) Ribbon structure of the ssion yeast TCTP ((Thaw et al., 2001); PDB: 1H6Q). The major domains are indicated in the gure. The colour coding is as in part (A). The microtubule-binding region is labelled in light blue. Dark blue regions mark those residues of the microtubule-binding region labelled blue in the mouse sequence in (A). The calcium-binding domain is not indicated; it is practically identical to the microtubule-binding region.

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Fig. 2. Regulation and functional importance of TCTP. This gure summarises the extracellular signals and conditions that result in regulation of TCTP levels and the cellular and extracellular importance of the protein. See text for details.

widely, depending on the cell/tissue type (Thiele et al., 2000) and on the developmental stage (Gnanasekar et al., 2002; Rao, Chen, Gnanasekar, & Ramaswamy, 2002). TCTP is expressed in mitotically active tissues, whereas expression levels are low in postmitotic tissue like brain (Thiele et al., 2000). In numerous experimental settings and biological systems, it was established that TCTP levels are highly regulated in response to a wide range of extracellular signals and cellular conditions (Fig. 2). Typically, growth signals (reviewed in (Bommer et al., 2002)) and cytokines (Nielsen, Johnsen, Sanchez, Hochstrasser, & Schiotz, 1998; Teshima, Rokutan, Nikawa, & Kishi, 1998) have been reported to rapidly induce TCTP synthesis. Various stress conditions, such as starvation (Bommer et al., 2002; Bonnet et al., 2000), heat shock, heavy metals, calcium stress (Xu, Bellamy, & Taylor, 1999) or proapoptotic/cytotoxic signals (Oikawa et al., 2002; Sinha et al., 2000) result in either up- or down-regulation of TCTP levels (see Bommer et al., 2002; Gachet et al., 1999 for further references). 3.2. Transcriptional and translational regulation The rapid adaptation of TCTP protein levels to alterations in cellular conditions implies that both synthesis and degradation are highly regulated. Concerning degradation one paper has been published,

reporting that the anti-apoptotic protein MCL1 stabilises TCTP (Zhang, Li, Weidner, Mnjoyan, & Fujise, 2002). However, there is plenty of evidence demonstrating that TCTP synthesis is regulated at both the transcriptional and the translational level. A study on about 50 human tissues (Thiele et al., 2000) and other investigations on TCTP mRNA levels demonstrated that the expression of this protein is transcriptionally regulated (reviewed in Bommer et al., 2002). Early reports on mammalian TCTP provided evidence for translational control of its synthesis: The mRNA was found in untranslated mRNP particles (Chitpatima et al., 1988), the growth-induced increase in the rate of TCTP synthesis preceded that of transcriptionally regulated proteins and it is not inhibited by actinomycin D (Boehm et al., 1989). Potential mechanisms of translational regulation that impinge on TCTP mRNA are discussed in Bommer et al. (2002); they include the growth-induced activation of initiation factor eIF-4E and of the ribosomal protein S6 kinase, the latter being implicated in the translational activation of 5 -TOP mRNAs. Due to its extended secondary structure, TCTP mRNA is also subject to negative translational regulation through the dsRNA-activated protein kinase PKR (Bommer et al., 2002).

4. Biological functions 4.1. Molecular interactions The rst molecular function of TCTP to be reported was calcium-binding activity (reviewed in Bommer et al., 2002). However, only recently has the (noncanonical) calcium-binding region been mapped (Kim et al., 2000). The tubulin-binding region was mapped to the same region (Fig. 1), and it was shown that in mammalian cells, part of TCTP is bound to microtubules during most of the cell cycle, inclusive of the metaphase spindle, but is detached from the spindle after metaphase (Gachet et al., 1999). This nding was recently corroborated by the demonstration that TCTP is phosphorylated by the protein kinase Plk (Yarm, 2002), which is likely to cause detachment of TCTP from the mitotic spindle. Other molecular interactions of TCTP published to date include selfinteraction (Yoon et al., 2000) and the interaction

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with the MCL1 protein (Zhang et al., 2002). The interaction of TCTP with various other proteins is documented in databases, although a unifying picture is not yet emerging. From communication with various colleagues, we know that TCTP frequently appears as an interacting protein in two-hybrid screens. Thus, more and very careful work is required to establish the complete array of molecular interactions of TCTP. 4.2. Cellular importance As TCTP levels are considerably up-regulated during entry of cells into the cell cycle, the protein is believed to be important for cell growth and division. This conclusion is conrmed by the following observations: (1) Overexpression of TCTP in mammalian cells resulted in slow growth and a delay in cell cycle progression (Gachet et al., 1999). (2) A genome-wide screen for phenotypes in Caenorhabditis elegans using RNAi (Kamath et al., 2003) established that knockdown of TCTP results in a slow-growth phenotype. (3) Overexpression of TCTP mutated in the phosphorylation sites for the mitotic kinase Plk (Fig. 1) disrupts the completion of mitosis (Yarm, 2002). (4) Gene-knockout of TCTP in ssion yeast resulted in cells compromised in entry into and exit from the cell cycle (Gachet and Hyams, personal communication). (5) Down-regulation of TCTP expression was found to be associated with reversion of cells from the transformed to the normal phenotype (Tuynder et al., 2002). The majority of publications describe TCTP as a cytoplasmic protein, but nuclear localisation has also been reported (Li et al., 2001). In ssion yeast, the latter has been found to be associated with cell stress (Gachet and Hyams, personal communication). TCTP levels are regulated in response to various stress conditions (see expression), and an increase in TCTP levels was reported to be associated with increased chemoresistance (Sinha et al., 2000; Walker et al., 2000). Overexpression of mammalian TCTP results in microtubule stabilisation and alteration of cell morphology (Gachet et al., 1999). Together with TCTPs similarity to chaperones (Thaw et al., 2001) and its recent characterisation as an anti-apoptotic protein (Li et al., 2001), these observations suggest that TCTP generally exerts a cytoprotective function. The cellular importance of TCTP is summarised in Fig. 2.

4.3. Extracellular activities In 1995, TCTP was described as a protein that triggers histamine release in basophil leukocytes and was called histamine release factor (HRF) by this group (MacDonald et al., 1995). Subsequent work has demonstrated that TCTP displays more general cytokine-like activities, as it also induces the production of interleukins from basophils and eosinophils (reviewed in (Bheekha-Escura, MacGlashan, Langdon, & MacDonald, 2000; MacDonald et al., 2001)). TCTP itself is induced by certain cytokines (see expression), and it acts as a growth factor for B-cells (Kang et al., 2001). Two important questions need to be addressed in this area: (1) How is TCTP secreted from cells? The TCTP mRNAs do not code for a signal sequence and no precursor protein has been described. (2) Through which receptor and signalling pathway does TCTP stimulate its target cells? The high conservation of TCTP from unicellular eukaryotes through to mammals and plants indicates that this cytokine-like function of TCTP was acquired only late in evolution. 5. Medical importance 5.1. Is TCTP a tumour protein? TCTP is not a tumour-specic protein, although its expression levels tend to be higher in tumours, compared to the corresponding normal tissue (Li et al., 2001; Tuynder et al., 2002), although this is not a general rule (Tuynder et al., 2002). The most convincing point in favour of a link between TCTP and cancer was provided by the demonstration that during reversion of cells from the malignant phenotype, TCTP levels are considerably reduced and that inhibition of TCTP expression results in suppression of the malignant phenotype (Tuynder et al., 2002). These ndings are in line with the importance of TCTP for cell growth and with its anti-apoptotic activity (Fig. 2). In this context it is interesting to note that TCTP levels are down-regulated through activation of the tumour suppressor protein p53 ((Tuynder et al., 2002) and our own unpublished data) and that TCTP is stabilised by the anti-apoptotic protein MCL1 (Zhang et al., 2002). Another interesting nding is the correlation of

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TCTP levels with the development of drug resistance in melanoma cells (Sinha et al., 2000). All these observations are based on preliminary studies, and more work will be necessary to establish whether TCTP might be suitable as a diagnostic tool or for other medical applications in connection with tumourigenesis. 5.2. Implication in other medical conditions In the initial characterisation of the histamine release activity (MacDonald et al., 1995), TCTP has been described as an IgE-dependent HRF for basophils implicated in the allergic late-phase reaction in atopic children. Later, it was shown that the HRF-triggered histamine release occurs independently of the IgE receptor (reviewed in Bheekha-Escura et al., 2000), that HRF/TCTP also induces the secretion of various interleukins (reviewed in MacDonald et al., 2001), and that it is able to induce B-cell activation (Kang et al., 2001). TCTP is therefore likely to be involved in a variety of inammatory processes. Decreased HRF/TCTP levels have been detected in certain areas of postmortem brains from Downs syndrome and Alzheimers patients, and this was related to distortions in the histaminergic system, observed in these conditions (Kim, Cairns, Fountoulakisc, & Lubec, 2001). However, it is difcult to directly establish a connection between the two observations, and it is also possible that diminished anti-apoptotic protection by TCTP is involved in this pathology. 5.3. TCTP in parasitic organisms TCTP has been characterised from various parasitic organisms, such as Plasmodium subspecies (Bhisutthibhan, Philbert, Fujioka, Aikawa, & Meshnick, 1999; Walker et al., 2000) and several parasitic worms (Gnanasekar et al., 2002; Rao et al., 2002). Two aspects are of medical importance: First, in all these cases, the parasitic TCTP protein is secreted in the host organism and is able to cause inammatory inltration of eosinophils (Gnanasekar et al., 2002; Rao et al., 2002) and/or histamine release from basophils (Rao, Chen, Gnanasekar, & Ramaswamy, 2002; MacDonald et al., 2001). Second, in Plasmodium, TCTP has been shown to directly bind the anti-malarial drug artemisinin, and increased TCTP expression correlated with increased resistance

against this drug (Walker et al., 2000). Thus it appears that the parasitic TCTP might be involved both in certain pathological processes in the infected host and in the development of drug resistance.

Acknowledgements Due to the format of this article series, it has not been possible to mention all papers that contributed to the TCTP story, and we wish to apologise to colleagues whose work could not be cited directly. We thank Professor Mike Clemens for comments on the manuscript. Work in our laboratories was funded by the Wellcome Trust (UAB) and the Deutsche Forschungsgemeinschaft (BJT). References
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