An eEF1A1 truncation encoded by PTI-1 exerts its oncogenic effect inside the nucleus

Abstract

BackgroundThe oncogene PTI-1 was originally isolated from a prostate cancer cell line by its capability to transform rat fibroblasts. The PTI-1 mRNA has a very eccentric structure as the 5′UTR is similar to prokaryotic 23S rRNA, while the major open reading frame and the 3′UTR corresponds to a part of the mRNA encoding human translation elongation factor eEF1A1. Thus, the largest open reading frame encodes a truncated version of eEF1A1 lacking the first 67 amino acids, while having three unique N-terminal amino acids. Previously, the UTRs were shown to be a prerequisite for the transforming capacity of the PTI-1 transcript. In this study, we have investigated the possible role of the UTRs in regulating protein expression and localization.MethodsThe protein expression profiles of a number of PTI-1 mRNA variants were studied in vitro and in vivo. Furthermore, the oncogenic potentials of the same PTI-1 mRNAs were determined by monitoring the capacities of stably transfected cells expressing these mRNAs to induce tumors in nude mice and form foci in cell culture. Finally, the cellular localizations of PTI-1 proteins expressed from these mRNAs were determined by fluorescence microscopy.ResultsThe PTI-1 mRNA was found to give rise to multiple protein products that potentially originate from translation initiation at downstream, inframe AUGs within the major open reading frame. At least one of the truncated protein variants was also found to be oncogenic. However, the UTRs did not appear to influence the amount and identities of these truncated protein products. In contrast, our localization studies showed that the UTRs of the transcript promote a nuclear localization of the encoded protein(s).ConclusionsTranslation of the PTI-1 mRNA results in multiple protein products of which (a) truncated variant(s) may play a predominant role during cellular transformation. The PTI-1 UTRs did not seem to play a role in translation regulation, but appeared to contribute to a nuclear localization of the PTI-1 protein(s). This indicates that the PTI-1 protein(s) exert(s) its/their oncogenic function inside the nucleus.

Improved Identification and Analysis of Small Open Reading Frame Encoded Polypeptides

“…pBLAST of this sequence demonstrated strong sequence homology of this SEP to a 462 amino acid long eukaryotic translation elongation factor 1 from residue 49 to 169. Truncated variants of EEF1A1 have previously been shown to promote 42 or suppress 43 cancer cell growth suggesting that this SEP266 might be an interesting candidate for downstream cell biological studies. The discovery of truncated forms of known proteins, such as EEF1A1, might provide new insight into the biological regulation of these proteins.…”

P21 activated kinase 4 binds translation elongation factor eEF1A1 to promote gastric cancer cell migration and invasion

“…eEF1A1 is involved in oncogenic transformation. It has been reported that an eEF1A1 truncation encoded by PTI-1 genes has oncogenic roles in transformation of NIH3T3 cells (44). Several differentially expressed gene screening have identified eEF1A1 involved in many types of cancers, such as cervical squamous cell carcinomas, lung squamous-cell carcinoma and breast cancer (45)(46)(47).…”

Tumor-Associated and Disease-Associated Autoantibody Repertoires in Healthy Colostrum and Maternal and Newborn Cord Sera

“…Note that most of the highly reactive, prevalent autoantibodies shown in Table I have some association with cancer-related selfAgs, including BIRC2 (41), CA125 (43), MUC1 (54), stem cell factor (60), S-100 (61), myosin (56), GHRH (26,27), glucagon (29), HGH (31), leptin (33), F3 coagulation factor III (36), EEF1A1 (45), fibronectin (48,49), neurotrophin-3 (58), BCMO1 (63), citrate synthase (66), GST (68), PTGDS (70), laminin (83), and MIF (85). Indeed, we have found that dynamic changes in autoantibody repertoires mark the natural history in mice of variants of a syngeneic, transplantable tumor (112).…”