Translation Elongation Factors: are Useful Biomarkers in Cancer? by Cristiano Luigi* in Open Access journal of Biogeneric Science and Research (JBGSR)
Abstract
The Eukaryotic Translation Elongation Factors are a large protein family involved in the elongation step of eukaryotic translation but it has also various moonlight functions inside the cell both in normal and in pathological conditions. The proteins included in this family are EEF1A1, EEF1A2, EEF1B2, EEF1D, EEF1G, EEF1E1, enclosed their various isoforms, i.e. PTI-1, CCS-3, HD-CL-08, and MBI‐eEF1A. They are proteins all bound to cancer development and progression and show gene amplification, genomic rearrangements, and alteration of expression levels in many kinds of cancers. These abnormalities have undoubtedly repercussions on cellular biology and cellular behaviour in the various step of transformation and progression of cancer but surely should be considered also for the enhancement of invasiveness and for the metastasis. Thus, the Eukaryotic Translation Elongation Factors may possibly useful biomarkers for human cancers although more studies are needed to better elucidate their exact contribution as diagnostic, prognostic, and progression markers.
Keywords: Eukaryotic translation elongation factors; translation; cancer; biomarker; EEF1A1; EEF1A2; EEF1B2; EEF1D; EEF1G; EEF1E1; EEF1H; PTI-1; EEF1A1L14; CCS-3; MBI‐eEF1A; HD-CL-08
Abbreviations: Alpha EEFs: Alpha 2. Eukaryotic Translation Elongation Factors; CCS-3: Cervical Cancer Suppressor 3; EEFs: Eukaryotic Translation Elongation Factors; eEF1A1: eukaryotic Translation Elongation Factor 1 alpha 1; eEF1A1L14: Eukaryotic Translation Elongation Factor 1-alpha 1-like 14; eEF1A2: eukaryotic translation Elongation Factor 1 alpha 2; eEF1B2: eukaryotic translation Elongation Factor 1 beta 2;eEF1D: eukaryotic translation Elongation Factor 1 delta; eEF1G: eukaryotic Translation Elongation Factor 1 gamma; eEF1E1: eukaryotic translation Elongation Factor 1 epsilon 1; eEF1H: eukaryotic translation Elongation Factor-1 macromolecular complex; HD-CL-08: cutaneous T-cell lymphoma antigen (similar to eEF1A1); MARS: Multiaminoacyl-tRNA synthetase macromolecular complex; MBI‐eEF1A: More Basic isoform of eEF1A; Non-alpha EEFs: not-alpha eukaryotic translation Elongation Factors;PTI-1: Prostate Tumor-inducing gene-1.
Background
Translation is one of the most important biological processes that take place into the cell because it permits genetic information to become functional proteins. It is formally divided into three main processes between them consequential: an initiation step, an elongation step, and a termination step. The Eukaryotic Translation Elongation Factors (EEFs) are a large protein family that plays a central role in the peptides’ biosynthesis during the elongation step of translation. This family counts different proteins and their isoforms and it is conventionally divided into two main subgroups: the Non-Alpha Eukaryotic Translation Elongation Factors (Non-alpha EEFs), that comprise the Eukaryotic Translation Elongation Factor 1 Beta 2 (eEF1B2), the Eukaryotic Translation Elongation Factor 1 Delta (eEF1D), the Eukaryotic Translation Elongation Factor 1 Gamma (eEF1G), and the Eukaryotic Translation Elongation Factor 1 Epsilon 1 (eEF1E1), including their isoforms, and the Alpha Eukaryotic Translation Elongation Factors (Alpha EEFs), that include the Eukaryotic Translation Elongation Factor 1 Alpha 1 (eEF1A1), Eukaryotic Translation Elongation Factor 1 Alpha 2 (EEF1A2), and their isoforms like the Prostate Tumor-Inducing Gene-1 (PTI-1), more recently renamed Eukaryotic Translation Elongation Factor 1-Alpha 1-Like 14 (EEF1A1L14), a more basic isoform of eEF1A1 (MBI‐eEF1A) , a cutaneous T-cell lymphoma antigen similar to eEF1A1 (HD-CL-08), and Cervical Cancer Suppressor (CCS-3).
The members of EEFs form a supramolecular complex named Eukaryotic Translation Elongation Factor-1 Macromolecular Complex (eEF1H) except for eEF1E1 that is a key component of another supramolecular complex, i.e. Multi-Aminoacyl-tRNA Synthetase Macromolecular Complex (MARS). eEF1H protein complex plays a central role in peptide elongation during eukaryotic protein biosynthesis, in particular for the delivery of aminoacyltRNAs to the ribosome mediated by the hydrolysis of GTP. In fact, during the elongation step of translation, the inactive GDP-bound form of eEF1A (eEF1A-GDP) is converted to its active GTP-bound form (eEF1A-GTP) by eEF1B2GDcomplex through GTP hydrolysis. Thus, eEF1B2GD-complex acts as a guanine nucleotide exchange factor (GEF) for the regeneration of eEF1A-GTP for the next elongation cycle [1- 3] (Figure 1).
FIGURE 1: The elongation step of translation. The active form eEF1A, in complex with GTP, delivers an aminoacylated tRNA to the A site of the ribosome. Following the proper codon-anticodon recognition the GTP is hydrolyzed and the inactive eEF1AGDP is released from the ribosome and then it is bound by the eEF1B2GD complex forming the macromolecular protein aggregate eEF1H. eEF1H is formed previously by the binding of three subunits: eEF1B2, eEF1G, and eEF1D. This complex promotes the exchange between GDP and GTP to regenerate the active form of eEF1A [1;4-8].
MARS protein complex, on the contrary, is formed by nine aminoacyl-tRNA synthetases (AARSs) and at least other three auxiliary non-synthetase protein components, [4-8] among which appears eEF1E1 [9-11]. eEF1E1 seems to contribute to the interaction and anchorage of MARS complex to EF1H complex during the elongation step of translation [11,12]. The EEFs show also multiple noncanonical roles, called moonlighting roles, inside the cell and they are all often altered in many kinds of cancer. Genomic rearrangements, gene amplification, novel fusion genes, point mutations, chimeric proteins, and altered expression levels were detected in many types of cancers and in other human diseases [13]. This wide spectrum of alterations for EEFs, common also for other genes and proteins, is frequently in cancer cells that are genetically more unstable respect to normal ones. Certainly, these abnormalities have repercussions on cellular biology and cellular behaviour in the various step of the malignancy transformation and progression. In the context of protein biosynthesis, the elongation step is doubtless accelerated and most likely loses fidelity and the control mechanisms fail or are less efficient. This can affect the worsening of the malignancy with direct and/or indirect repercussions on the progression of cancer, including the increase in invasiveness and, finally, in the metastasis. The purpose of this work is to briefly summarize the main studies in which the role of these proteins in tumor transformation has been identified in order to be able to start from here for further studies and analyzes.
Non-Alpha Eukaryotic Translation Elongation Factors
Non-alpha EEFs include most of the proteins that contribute to the translation elongation step in eukaryotes. These are eEF1B2, eEF1D, eEF1G, eEF1E1, and their isoforms. Here it will deal exclusively with the main proteins, excluding the isoforms because the studies on cancer are in their infancy for them. The expression levels for each member are shown in Table 1.
Table 1: List of EEFs and some of their most important isoforms with their expression levels in cancers.
EEF1B2
EEF1B2, also known as EEF1B1 or eEF1β or eEF1Bα, was identified for the first time by Sanders and colleagues in 1991 [14]. It is the smallest subunit of EEF1H complex and among his moonlight roles are counted the control on the translation fidelity [2], the inhibition of protein synthesis in response to stressors, and the interaction with the cytoskeleton [15,16]. Gene expression for EEF1B2 was observed to be altered in many cancer types, in fact, it is frequently found overexpressed. Furthermore, EEF1B2 counts various kinds of genomic translocations and numerous fusion genes [1] [17-50].
EEF1D
EEF1D, also known as eEF1Bdelta, was identified for the first time by Sanders and colleagues in 1993 [50]. Four isoforms were detected, produced by alternative splicing: isoform 1, also called eEF1DL, of 647 residues, and isoform 2, of 281 amino acids, are the better known [51]. Its moonlight roles included its role as a transcriptional factor and its involvement in the stress response [51-54]. It is involved in a very large number of genomic translocations (and fusion genes) in different kinds of tumors and it was frequently found overexpressed. It was demonstrated that an increase in its expression level has an oncogenic potential with resulting in cell transformation [55]. Therefore, it is considered a cellular proto-oncogene [56].
EEF1G
EEF1G, also known as eEF1γ or eEF1Bγ, was identified for the first time by Sanders and colleagues in 1992 [57]. There are known two isoforms produced by alternative splicing: isoform 1 (chosen as canonical), by 437 residues, and isoform 2, of 487 amino acids [58]. Its moonlight roles included the interaction with the cytoskeleton [27,59] and some nuclear and cytoplasmic proteins, such as RNA polymerase II [60], TNF receptor-associated protein 1 [61] and membrane-bound receptors [62]. In addition, it has mRNA binding properties [60-63] and it is a positive regulator of the NF-kB signalling pathway [64]. It is involved in some genomic translocations (and fusion genes) in different kinds of tumors and it was frequently found overexpressed.
EEF1E1
EEF1E1, also known as p18 or AIMP3, was identified for the first time by Mao and colleagues in 1998 [65]. It is the smallest component of the MARS complex [66] and it has various moonlight roles inside the cell: it seems to play a role in mammalian embryonic development [67], in the DNA damage response [68], and in the degradation of mature Lamin A [69]. A great number of mutations in the genomic sequence and in the amino acid sequence for EEF1E1 were discovered in cancer cells as well as genomic translocations, novel fusion genes, and altered expression levels.
Alpha Eukaryotic Translation Elongation Factors
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EEF1A1
EEF1A1, or EEF1α or EF-1α, is one of the most studied translation elongation factors. It is present in almost all cell types, with some exceptions, as it plays a key role in the translation process, i.e. in eukaryotes, it promotes the binding of aminoacyl-tRNA (aa-tRNA) to the 60S subunit of the ribosome during the elongation process of the protein synthesis. To carry out its function it consumes a molecule of GTP, becoming inactive, and therefore needs to be recharged in its active form by the eEF1B2GD complex [2,3]. It has various moonlight functions, including cytoskeleton remodelling [70], promotion of misfolded protein degradation [71], control of the cell cycle [72], and the promotion of apoptosis [72]. EEF1A1 is often amplified and overexpressed in cancers [72]. This is related not only to its key role in protein synthesis but also to its many moonlight functions.
MBI‐eEF1A
A more basic isoform of eEF1A1, alias MBI‐eEF1A, was identified for the first time by Dapas and colleagues [36] in human haematopoietic cancer cell lines. This finding opens the possibility that also the post-translation modifications of eEF1A1 could be related to cancer development and/or progression and should be deeply studied [73].
PTI-1
PTI-1 was identified for the first time by Shen and colleagues in 1995 [74] and it shows similarities to eEF1A from whose amino acid sequence it differs for having lost 67 amino acids at the N-terminal region. Initially considered a specific oncogene for prostate cancer, it later turned out to be unrelated but instead to be due to the infection of the cells by some species of bacteria belonging to the genus Mycoplasma, in particular Mycoplasma hyorhinis [75]. The exact role of PTI-1 is unknown but it has been suggested that it might reduce translational fidelity and so concur or bring to tumorigenesis [76].
CCS-3
CCS-3 was identified for the first time by Rho and colleagues in 2006 [43] and it shows similarities to eEF1A from whose amino acid sequence it differs for having lost 101 amino acids at the N-terminal region. Its expression level is found to be very low to undetectable in human cervical cancer cells while is it higher in normal human cell lines. The functions of CCS-3 are still poorly understood, however from the studies carried out to date it seems that it may play a role as a transcriptional repressor [43-77]. Furthermore, low levels of its expression appear to prevent apoptosis so it could have also an anti-tumor activity [43].
HD-CL-08
It was discovered that a cutaneous T-cell lymphoma antigen, named HD-CL-08, shows high sequence homology with eEF1A1, but it lacks 77 amino acids in the NH2-terminal portion [43-78].
EEF1A2
EEF1A2 is analogous to EEF1A1 and its expression is normally found only in some tissues, where it completely replaces EEF1A1, i.e. adult brain, heart, and skeletal muscle [79]. It is not expressed in other tissues under physiological conditions. The study of the role of EEF1A2 in the tumor transformation process has been conducted in many tumors, but the most characterizing researches have been carried out in ovarian and breast cancers. EEF1A2, in fact, is considered to be a putative oncogene in ovarian cancer [46]. Like EEF1A1, EEF1A2 is also highly expressed in many cancer types and its amplification is related to a poor clinical prognosis and an increase in tumor aggressiveness [72].
Conclusion
The family of The Eukaryotic Translation Elongation Factors has been studied for over thirty years and although data on expression levels are controversial among the studies, the large number of research and publications in the literature suggests that EEFs participate actively in tumorigenesis and so they may possibly useful biomarkers for human cancers. What needs to be clarified and better defined in an incontrovertible way is in which phase of the evolution of cancer they can make the greatest contribution and have the greatest role, i.e. being able to use them as diagnostic, prognostic and progression markers, but not only. They should be studied and evaluated also as indicators for the risk assessment, screening, differential diagnosis, prediction of response to treatment, and monitoring of metastases.
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