One Drug Target for Several Diseases?

The Translationally Controlled Tumor Protein (TCTP)

  • Fig. 1: Structure of Schizosachharomyces pombe-TCTP The TCTP molecule consists of a helical domain (left in pink), a ß-stranded core domain containing the triangle formed of three amino acids which are important for binding Rab proteins (middle in turquoise with highlighted residues in yellow) and a high-flexible loop region (right in blue). The region between the amino acids 79-123 forming the helical domain are shown to be essential for Tubulin binding.Fig. 1: Structure of Schizosachharomyces pombe-TCTP The TCTP molecule consists of a helical domain (left in pink), a ß-stranded core domain containing the triangle formed of three amino acids which are important for binding Rab proteins (middle in turquoise with highlighted residues in yellow) and a high-flexible loop region (right in blue). The region between the amino acids 79-123 forming the helical domain are shown to be essential for Tubulin binding.
  • Fig. 1: Structure of Schizosachharomyces pombe-TCTP The TCTP molecule consists of a helical domain (left in pink), a ß-stranded core domain containing the triangle formed of three amino acids which are important for binding Rab proteins (middle in turquoise with highlighted residues in yellow) and a high-flexible loop region (right in blue). The region between the amino acids 79-123 forming the helical domain are shown to be essential for Tubulin binding.
  • Fig. 2: Multiple sequence alignment of TCTP sequences from a multitude of species The multiple sequence alignment was performed using ClustalX version 1.83, whereas GenDoc software (Version 2.6) was used for coloring. The Neighbor-Joining based taxonomic tree was calculated and visualized using PHYLIP software package and TreeView.  Sites having all amino acids are equal or similar are highlighted in red. Less conserved sites are colored yellow or grey if at least 10 or 7 out of 12 amino acids in a column are equal or similar. The sequences for the alignment are taken from www.ebi.ac.uk.
  • Fig. 3a: TCTP involved processes: Many different cellular processes are influencing TCTP function and expression levels (3a). Due to these influences TCTP is able to regulate several downstream processes (3b).
  • Fig. 3b: TCTP involved processes: Many different cellular processes are influencing TCTP function and expression levels (3a). Due to these influences TCTP is able to regulate several downstream processes (3b).

TCTP is a highly conserved protein that is expressed ubiquitary in eukaryotic organisms. Based on the structure of Schizosachharomyces pombe - TCTP was assigned to small family of chaperones. TCTP is implicated in cell cycle progression, malignant transformation and in the response of cells to various stress conditions and apoptosis. Upregulation was shown in different cancer tissues and in addition, an extracellular, histamine releasing function has been discovered for TCTP.

History


The translationally controlled tumor protein was mentioned for the first time in investigations from the 1980´s, initially identified in mammalian tumor cells and named Q23 (depending on the run length on a gel). Experiments using actinomycin D as transcription inhibiting agent resulted in no difference in the synthesis rate of this protein. This has left the only explanation that this protein must be regulated on the translational level. Short time after the first description, the same protein was named p21 in publications and even the induction of expression by actinomycin D could be elucidated. Finally, being named Fortilin, Q23, p23 and p21, in 1989 the name was changed to „translationally controlled tumor protein" because of its first detection in cancer cells and the confirmed regulation at the translational level. But, having an extracellular function as a histamine release factor has made "histamine releasing factor (HRF)" a synonym for TCTP [6]. Nowadays, and many investigations later, it is clear that TCTP is not a cancer specific appearance but is ubiquitary expressed in all eukaryotic organisms, from plants over one cell organisms like Plasmodium spec. to mammalians. Recently, TCTP has caught the attention of an increasing number of researchers in the biology and medicine related fields because TCTP levels vary in response to a wide range of extracellular stimuli. A series of publications has shown the importance of TCTP for cell cycle and malignant transformation, apoptosis and extracellular function as a histamine release factor.

Structure

The translationally controlled tumor protein consists of 170 amino acids in average and has a mean weight of 19.4 kDa.

Because of the strong conservation between different species, it can serve as phylogenetic marker which is already discussed in recent papers on phylogenetics. A mutiple sequence alignment demonstrates that conservation impressively (fig. 2).
The highly conserved sequence of TCTP and its existence in a multitude of species confirmed the essential function for the organisms. The N-terminal region of the protein plays an important role in its antiapoptotic activity and is therefore strongly conserved. Despite the importance of that molecule, its molecular function has remained elusive.
In 2001, the structure of Schizosachharomyces pompe - TCTP could be determined by NMR analysis [1]. Interestingly, TCTP seems to be similar to the human guanine-nucleotide-free chaperone Mss4 which is interacting with GDP/GTP-free proteins of the Rab family. Especially the amino acids 12, 74 and 134 are forming a triangle which can be found mostly equal in the Sec4 binding site of Mss4. Furthermore, a tubulin-binding region could be identified between the amino acids 79-123 in human, murine, rat and rabbit TCTPs being similar to the binding site of microtubule-associated protein 1B [2] (fig. 1).
Posttranslational modification sites have been described only for serine phorphorylation at position 46 and 64 in human TCTP [3]. A Polo-like kinase is responsible for the modifications what seems self-explanatory if we consider that this enzyme group is mostly phosphorylating cytoskeleton binding proteins. The absence of phosphorylated sites results in abnormal cell growth.

Function

A multitude of interactions of TCTP with other proteins were elucidated. Using this informations and even from RNA - level allows us to create a rough image of the processes that affect TCTP and are affected by it (fig. 3).

Clinical Relevance

As previously mentioned, TCTP is ubiquitously expressed in all eukaryotic organisms. Thus, theoretically it could not only serve as drug target in treatment of cancer but also of several diseases caused by parasites.
Up-regulated levels of TCTP can be found in cancer cells of different tissues [4, 5]. From the perspective of cancer scientists, the effect of TCTP on Leukemia-1-protein (Mcl-1) is a great discovery. Mcl-1 is a protein that is characterized by its instability and due to that fact, it induces cell death if not stabilized. Indeed, it could be shown that TCTP is responsible for the stabilization of Mcl-1 and can even increase the antiapoptotic effect of that protein [6]. Antiapoptotic activity is further increased by antagonizing bax function of TCTP. Even the human telomerase is positively affected by TCTP and would explain a further role of TCTP in the progression of cancer cells [7]. Furthermore TCTP gets secreted in non-classical ways and is involved in inflammatory processes as histamine releasing factor (HRF) [8] and acts in the cellular response to oxidative stress as scavenger for radicals [9]. Another interesting discovery is the correlation of TCTP expression with chemoresistance in melanoma cells. This and other evidences made TCTP to one of the most interesting molecules for tumor reversion [10].
Nevertheless, this protein is interesting for therapy of different kinds of diseases, for instance for the ones which are caused by parasites or fungi.
In human malaria treatment, artemisinin is the current drug of choice and it could be shown that TCTP is a target of this drug in the parasite cell [9]. Therefore, a lead drug structure exists to design more effective compounds depending on this. TCTP molecules are initially investigated in the parasites Brugia malayi and Trichinella spiralis. Chagas disease and leishmaniasis are other serious diseases, which could be treated with a TCTP targeted approach but there are no investigations performed in that direction yet.
In principle, the use of TCTP as target molecule seems to be endless but many more investigations on the function and characterization of TCTP are of urgent need. Although there are many hints for the importance of this protein, a complete description of the function in the cell is still to be elucidated.
In matters of TCTP based drug development, it is known that artemisinin targets TCTP but it is unsolved if this interaction is mostly responsible for cell death after treatment. Furthermore the interaction between artemisinin and TCTP needs to be clarified on molecular level in order to use it as a template for new therapeutic approaches.

References

[1] Thaw et al.: Nat Struct Biol 8 (8), 701-704 (2001)
[2] Gachet et al.: J Cell Sci 112 (Pt 8), 1257-1271 (1999)
[3] Yarm: Mol Cell Biol 22 (17), 6209-6221 (2002)
[4] Slaby et al.: Oncol Rep 21 (5), 1235-1241 (2009)
[5] Kim et al.: Exp Mol Med 40 (6), 709-720 (2008)
[6] Zhang et al.: J Biol Chem 277 (40), 37430-37438 (2002)
[7] Keppler et al.: J Biol Chem 281 (29), 19840-19848 (2006)
[8] Amzallag et al.: J Biol Chem 279 (44), 46104-46112 (2004)
[9] Bhisutthibhan et al.: J Biol Chem 273 (26), 16192-16198 (1998)
[10] Telerman and Amson: Nat Rev Cancer 9 (3), 206-216 (2009)

Authors:
Tolga Eichhorn, MSc, PhD student 1,2
Thomas Efferth, PhD, Professor 1
1 University of Mainz, Department of Pharmacy and Biochemistry, Pharmaceutical Biology
2 German Cancer Research Center (DKFZ), W160 - Molecular structure analysis

 

 

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University of Mainz - Department of Pharmacy and Biochemistry Pharmaceutical Biology
Staudingerweg 5
55128 Mainz, Rheinland-Pfalz
Germany

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