PTI-1: novel way to oncogenicity

Vislovukh, A. A.; Shalak, V. F.; Savytskyi, Oleksandr V.; Kovalenko, N. I.; Gralievska, N. L.; Negrutskii, B. S.; El'skaya, A. V.

doi:10.7124/bc.00006c

Cited by 3 publications

(4 citation statements)

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“…The results appear controversial, but may depend on cell type [ 3 , 5 , 14 ]. A theoretical study suggests the expression of a relaxin homolog from an uORF with potential influence on prostate cancer progression [ 15 ]. However, no experimental studies have so far addressed the possible expression of truncated proteins from the PTI-1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

“…The expression of a small peptide (approx. 4.6 kDa) from a uORF as suggested in a computational analysis of the expression potential of the PTI-1 mRNA [ 15 ] could not be confirmed in vitro (Figure 2 B), but cannot be excluded to occur in vivo .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…This change of their expression is crucial, as the mice with a partial deletion of the EEF1A2 gene die on the 28 th day after birth [3]. Despite the same catalytic efficacy during the elongation step of protein biosynthesis, the isoforms seem to be different in their non-canonical functions [4][5][6]. eEF1A1 demonstrates proapoptotic properties, while eEF1A2 has anti-apoptotic, pro-oncogenic characteristics [7][8][9].…”

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Isoforms of elongation factor eEF1A may be differently regulated at post-transcriptional level in breast cancer progression

et al. 2013

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Eukaryotic translation elongation factor 1A exists as two 98 % homologous isoforms: eEF1A1 (A1) and eEF1A2 (A2) which are tissue and development specific. Despite high homology in an open reading frame (ORF) region, mRNAs coding for eEF1A1 and eEF1A2 are different in their untranslated regions (UTR), suggesting a possibility of their dissimilar post-transcriptional regulation. Aim. To analyze the existence of cis-acting motifs in the UTRs of EEF1A1/A2 mRNAs, to confirm the possibility of post-transcriptional control of eEF1A1 and eEF1A2 expression. Methods. An ensemble of bioinformatic methods was applied to predict regulatory motifs in the UTRs of EEF1A1/A2 mRNAs. Dual-luciferase reporter assay was employed to detect post-transcriptional regulation of eEF1A1/A2 expression. Results. Numerous regulatory motifs in the UTR of EEF1A1/A2 mRNAs were found bioinformatically. The experimental evidence was obtained for the existence of negative regulation of EEF1A1 and positive regulation of EEF1A2 mRNA in the model of breast cancer development. Conclusions. EEF1A1 and EEF1A2 mRNAs contain distinct motifs in the UTRs and are differently regulated in cancer suggesting the possibility of their control by different cellular signals

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“…Importantly, in such case this assumed peptide resembles the active center of relaxin, the peptide hormone involved in the prostate cancer progression [53]. However, as much as this idea is attractive it needs a credible experimental evidence.…”

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Specific features of protein biosynthesis in higher eukaryotes

et al. 2013

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Over 40 years of studies in the field of higher eukaryotic translation are summarized in the review. Among the pioneer results obtained we should especially accentuate the following: i) discovery of the adaptation of tRNAs and aminoacyl-tRNA synthetases (ARSs) cellular pools to the synthesis of specific proteins and modulation of the elongation rate by rare isoacceptor tRNAs; ii) the chaperone-like properties of the translation components (ribosomes and elongation factor eEF1A); characterization of high molecular weight complexes of ARSs; iii) functional compartmentalization, including channeling of tRNA in eukaryotic cells; iv) molecular mechanisms of channeling mediated by different non-canonical complexes involving eEF1A, tRNA and aminoacyl-tRNA synthetases; v) characterization of the crystal structure of eEF1A2; vi) comparison of spatial structure, molecular dynamics, tyrosine phosphorylation and abilities to interact with different protein partners of the eEF1A1 and eEF1A2 isoforms; vii) discovery of the microRNA-mediated control of the expression of the proto-oncogenic eEF1A2 isoform in cancer cells; viii) examination of the cancer-related changes in translation elongation complex eEF1H and mechanisms of oncogene PTI-1 action; ix) discovery of the third tRNA binding site on mammals ribosomes and the allosteric interaction of the 80S ribosomal A and E sites

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PTI-1: novel way to oncogenicity

Cited by 3 publications

References 46 publications

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

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

Isoforms of elongation factor eEF1A may be differently regulated at post-transcriptional level in breast cancer progression

Specific features of protein biosynthesis in higher eukaryotes

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