The eukaryotic elongation factor 1 subunit gamma (eEF1Bγ), also known as the pancreatic tumor-related protein, is a part of the eEF1 multiprotein macromolecular complex. The eEF1 holoenzyme plays a role in protein synthesis by recruiting the aminoacyl-tRNAs to the A site of the ribosome [
1]. Using the current nomenclature for higher eukaryotes, eEF1 consists of two different sub-complexes: eEF1A and eEF1B. eEF1A (formerly eEF1α) is a single polypeptide, whereas eEF1B is a multimer of eEF1Bα (formerly eEF1β), eEF1Bδ (formerly eEF1δ), and eEF1Bγ (formerly eEF1γ). There is evidence to indicate that eEF1Bγ stimulates, but is not required for, the catalytic activity of eEF1Bα [
2,
3]. Indeed, eEF1Bγ appears dispensable for translation, and its absence does not seem to affect the global rate of translational elongation [
4,
5]. Nevertheless, multiple non-canonical roles for eEF1Bγ are emerging, some of which can be regulated by phosphorylation driven by several protein kinases [
6]. A role of eEFB1γ in the oxidative stress response pathways is justified by the presence in the N terminus of a conserved sequence resembling the glutathione-binding region of the theta class of glutathione S-transferase (GST) enzymes, which are involved in the detoxification of oxygen radicals. The over-expression of the eEF1Bγ gene product has been reported in several tumors, including pancreatic, breast, colon, and gastric tumors [
7‐
11]. There is growing evidence that the elongation step is also regulated in response to environmental cues, supporting the idea that deregulation of translational control serves as a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development [
12,
13]. In a wider context, aberrant proliferation of cancer cells is supported by adaptation to nutrient microenvironment mediated by a dynamic metabolic reprogramming [
14]. Importantly, the level of eEF1Bγ upregulation was shown to positively correlate with tumor aggressiveness, presumably due to an altered redox balance [
2,
15,
16]. eEF1Bγ displays an affinity for membrane and cytoskeleton elements, and it can properly anchor the different subunits of the EF1 complex to the cytoskeleton [
2,
6,
17]. Interestingly, Al-Maghrebi et al. (2002) demonstrated the RNA-binding properties of eEF1Bγ by showing for the first time its binding to the 3’ UTR of vimentin mRNA [
18], suggesting that eEF1Bγ could exert many of its biological functions through the binding of a pool of mRNAs. In addition, human eEF1Bγ was recently identified in a proteomic screen as a member of the pre-mRNA 3’ end cleavage complex [
19]. In this context, eEF1Bγ could participate in the anchoring and translation of a set of mRNAs that are preferentially translated on cytoskeletal- or membrane-bound ribosomes, such as vimentin mRNA. Vimentin has been recently reported to have a regulatory role in supporting the morphology, organization and function of mitochondria [
20,
21]. Importantly we previously demonstrated that eEF1Bγ partially co-localizes with mitochondria [
5]. Yoo’s research group showed that hCdc73, a component of the human RNA polymerase II-associated factor complex (PAFc), binds and destabilizes p53 mRNA via eEF1Bγ, thus acting as a binding platform [
22]. They proposed that mis-regulation of this interaction may lead to tumor progression. Liu et al. reported a new role for eEF1Bγ in the activation of the NF-Kb signaling pathway, through targeting the mitochondrial antiviral adaptor protein (MAVS), which bridges viral RNA recognition and downstream signal activation [
23]. The Esposito research group showed that the TNF receptor associated protein (TRAP1), a mitochondrial member of the HSP90 family, which is involved in the protection of oxidative stress, selectively binds eEF1Bγ, and, remarkably, both TRAP1 and eEF1Bγ are co-upregulated in human colorectal cancers [
24]. We have previously shown that eEF1Bγ interacts with the RNA polymerase II (pol II) alpha-like subunit “C” (POLR2C), alone or complexed, in pol II [
25‐
27]. The POLR2C/POLR2J heterodimer (also called RPB3/RPB11) is reminiscent of the α subunit homodimer of bacterial RNA polymerase [
28]. In bacteria, the alpha subunit homodimer associates with σ factors that mediate promoter recognition [
29‐
31]. Moreover, eEF1Bγ has been described to bind the vimentin 3’ UTR, and we have shown that it also binds the promoter region of the vimentin gene [
5,
18]. These results suggest that eEF1Bγ has a role in shuttling/nursing vimentin mRNA (and presumably a specific set of mRNAs) from their gene locus to their appropriate cellular compartment for translation. On the basis of eEF1Bγ sub-cellular localization and its involvement in RNA metabolism and mitochondria/cytoskeleton organization, herein, using a mitochondria-enriched heavy membrane (HM) fraction, we identified, by ribonucleoprotein complex immunoprecipitation (RIP assay), several novel transcripts that complexed with eEF1Bγ. Among the isolated mRNAs, we found genes involved in translation and in mitochondrial/cytoskeleton metabolism. In particular, we found the mRNA of the pol II binding protein Che-1/AATF, and we confirmed the presence of the p53 transcript [
22]. Che-1 plays a role in multiple fundamental processes, including control of transcription, cell cycle regulation, DNA damage responses and apoptosis [
32‐
34]. Recent studies suggest that Che-1 protein level dysregulation could be relevant for the transformation process. Che-1 is found upregulated in several leukemia cell lines and in patient with chronic lymphocytic leukemia [
33].
Here, we show for the first time that eEF1Bγ binds to the Che-1 and TP53 promoter regions. In addition, we describe a novel mitochondrial localization for the Che-1 protein, and we show that Che-1 needs mitochondrial integrity for correct localization. We suggest a role for eEF1Bγ as a primordial transcription/translation factor that links the fundamental steps between transcription control and local translation.