*3.2. Translational Regulation*

TCTP was originally discovered by the fact that its synthesis is induced after serum-stimulation of murine cells by translational activation of its preformed mRNA [1]. By 2016, several additional examples of translational regulation of TCTP synthesis were reported (reviewed in [5]), and among these, two principal translational control mechanism were found to be involved: (1) the growth factor-related induction of TCTP synthesis via the mTORC1-eIF4E signalling pathway [60,61], and (2) the negative regulation of TCTP synthesis via activation of PKR and eIF2 α-phosphorylation. The latter occurs under serum-starvation [62] and also under Ca2<sup>+</sup>-stress conditions [63]. Our original observation that TCTP mRNA is a highly structured molecule that binds to and activates PKR [62] was further confirmed by a recent structural analysis of this mRNA under a various conditions, inclusive of the influence of riboSNitches [64].

Similarly, the regulation of TCTP synthesis through mTORC1 was recently observed in a very specific biological system, the retinal axon. Based on the findings from genome-wide screens, that TCTP mRNA is one of the most abundant mRNAs localised in the growth cone of axons, Roque et al. studied the role of TCTP in the development of the retinal axon in *Xenopus laevis*. They showed that it is indeed a protein essential for the normal development of the visual circuitry in the frog [18]. In a follow-up paper, the authors specifically investigated the translational regulation of TCTP and its importance for axon guidance [17]. They demonstrated that in axons of retinal ganglion cells, local TCTP synthesis is regulated by two axon guidance cues in an mTORC1-dependent fashion. In a completely di fferent biological system, the intestinal stem cells in the midgut of *Drosophila*, ye<sup>t</sup> another example of posttranscriptional regulation of TCTP synthesis was observed [15]. In this case, the Hippo signalling pathway has been implicated. However, the precise mechanism still awaits further characterisation.

The two translational control mechanisms referred to so far that target TCTP mRNA, act on the 5--TOP (the mTORC1 signalling pathway), or on the highly structured area of the mRNA (for PKR activation). The latter most likely comprises the CG-rich 5--UTR and a 5--terminal stretch of the coding region [64]. Other translational control modes, targeting the 3--UTR of TCTP mRNA, emerged only recently. This is surprising, since for 20 years, we have known that in many organisms, TCTP mRNA occurs in two isoforms, which differ in the length of their 3--UTRs [65], with the shorter isoform usually being the most abundant one. Therefore, the biological importance of the second isoform is still elusive. In addition, for the regulation of TCTP expression in the axonal growth cone, it was shown that it is the shorter isoform, which is subject to translational regulation [17]. The first example of regulation of TCTP expression via the 3--UTR of its mRNA was revealed in a recent, very interesting report [66]. The authors studied the expression of TCTP in *Trypanosoma brucei* and found that this unicellular parasite during its life cycle differentially expresses two TCTP paralogs, TCTP1 in the procyclic life form (in the tsetse fly) and TCTP2 in the blood stream form in humans. The two mRNAs largely differ in their 3--UTRs, with TCTP2-mRNA bearing a 1.5-fold longer one. The authors demonstrated that the 3--UTRs confer differential stability to these TCTP mRNA isoforms and that, for TCTP2 mRNA, the *cis*-acting element largely resides in the first 160 nucleotides of the 3--UTR. However, the precise characterisation of the *cis*-acting element awaits further investigation.



Another mode of posttranscriptional regulation that targets individual mRNAs, typically via their 3--UTRs, is the regulation by micro-RNAs. These short RNA molecules recruit 'their' target mRNAs to the RNA-induced silencing complex (RISC), which leads to translational arrest or even degradation of the mRNA. However, information about validated cases of TCTP mRNAs being regulated in this way is scarce (Table 2). In 2012, two papers reported that TCTP mRNA is regulated by miRNAs, i.e., miR-130a [67] and miR-27b [68], respectively. In the latter case, the authors observed that miR-27b levels were significantly reduced in tumor tissue of oral cancer patients, resulting in an increase of TCTP protein expression. Similarly, two recent papers reported on the deregulated TCTP expression in cancer, due to low levels of certain miRNAs, i.e., miR-145-5p in prolactinoma [69] and miR-125-3p in lung cancer [70]. In the latter paper, the authors studied the induction of TCTP in lung cells by tobacco smoke carcinogens. They found that miR-125-3p, is able to prevent the expression of a TCTP 3--UTR reporter gene construct and that this miRNA is significantly down-regulated in xenografts generated from cells pretreated with these carcinogens.
