The Role of Acetylation in the Subcellular Localization of an Oncogenic Isoform of Translation Factor eIF5A

Ishfaq, Muhammad; Maeta, Kazuhiro; Maeda, Satoko; Natsume, Tohru; Ito, Akihiro; Yoshida, Minoru

doi:10.1271/bbb.120620

Cited by 22 publications

(28 citation statements)

References 15 publications

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“…In addition, eIF5A can be modified by transglutaminylation [24], acetylation [25, 26] and phosphorylation [27, 28], but clear effects on its activity have not been detected.…”

Section: Formation and Role Of Hypusinementioning

confidence: 99%

The translation factor eIF5A and human cancer

Mathews

Hershey

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

146

155

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SUMMARY The eukaryotic initiation factor eIF5A is a translation factor that, unusually, has been assigned functions in both initiation and elongation. Additionally, it is implicated in transcription, mRNA turnover and nucleocytoplasmic transport. Two eIF5A isoforms are generated from distinct but related genes. The major isoform, eIF5A1, is considered constitutive, is abundantly expressed in most cells, and is essential for cell proliferation. The second isoform, eIF5A2, is expressed in few normal tissues but is highly expressed in many cancers and has been designated a candidate oncogene. Elevated expression of either isoform carries unfavorable prognostic implications for several cancers, and both have been advanced as cancer biomarkers. The amino acid hypusine, a presumptively unique eIF5A post-translational modification, is required for most known eIF5A functions and it renders eIF5A susceptible to inhibitors of the modification pathway as therapeutic targets. eIF5A has been shown to regulate a number of gene products specifically, termed the eIF5A regulon, and its role in translating proline-rich sequences has recently been identified. A model is advanced that accommodates eIF5A in both the initiation and elongation phases of translation. We review here the biochemical functions of eIF5A, the relationship of its isoforms with human cancer, and evolving clinical applications.

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“…In addition, eIF5A can be modified by transglutaminylation [24], acetylation [25, 26] and phosphorylation [27, 28], but clear effects on its activity have not been detected.…”

Section: Formation and Role Of Hypusinementioning

confidence: 99%

The translation factor eIF5A and human cancer

Mathews

Hershey

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

146

155

View full text Add to dashboard Cite

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“…This antagonism illustrates the potential for hierarchies and cross-talk between PTMs [48,49]. It is therefore intriguing that eIF5A1 is also apparently subject to multiple additional acKs (Table 1), including on Lys 49 , immediately proximal to the hypusinated Lys 50 , all of which await functional characterization.…”

Section: Dead-box Polypeptidementioning

confidence: 99%

“…eIF5A1 undergoes nucleocytoplasmic shuttling and its cytoplasmic functions, studied largely in yeast and non-mammalian vertebrates, include translation elongation and mRNA turnover. Nascent eIF5A1 protein is transported to the nucleus where its hypusination (hyp) at Lys 50 (hypK 50 ) leads to its nuclear export and cytoplasmic retention [47][48][49]. Although hyp is irreversible, eIF5A1 can also be acetylated at Lys 47 , which antagonizes Lys 50 hyp and prevents its nuclear export, thereby providing a mechanism to regulate eIF5A1 sub-cellular localization.…”

Section: Dead-box Polypeptidementioning

confidence: 99%

“…Although hyp is irreversible, eIF5A1 can also be acetylated at Lys 47 , which antagonizes Lys 50 hyp and prevents its nuclear export, thereby providing a mechanism to regulate eIF5A1 sub-cellular localization. Furthermore, both Lys 50 hyp and retention of the positive charge state of Lys 47 are essential for its translational functions [48,49] and Lys 47 acetylation therefore provides a fail-safe mechanism to abrogate eIF5A-dependent translation should any nonhypusinated protein escape into the cytoplasm.…”

Section: Dead-box Polypeptidementioning

confidence: 99%

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Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered?

Blee

Gray

Brook

2015

Biochemical Society Transactions

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Post-transcriptional control of gene expression is critical for normal cellular function and viability and many of the proteins that mediate post-transcriptional control are themselves subject to regulation by posttranslational modification (PTM), e.g. phosphorylation. However, proteome-wide studies are revealing new complexities in the PTM status of mammalian proteins, in particular large numbers of novel methylated and acetylated residues are being identified. Here we review studied examples of methylation/acetylationdependent regulation of post-transcriptional regulatory protein (PTRP) function and present collated PTM data that points to the huge potential for regulation of mRNA fate by these PTMs.

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“…EIF5A has been demonstrated to serve a role in translation initiation, translation elongation, transcription, mRNA turnover and nucleocytoplasmic transport (5). EIF5A arises in two forms (6,7); EIF5A1 serves an essential role in non-malignant cells, although it has also been implicated in cancer (8). EIF5A2 is a purported oncogene that is less widely expressed in normal tissue (5,9,10); however, EIF5A2 expression has been associated with a number of cancer types, including lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

Chen

Zhang

et al. 2018

Oncol Lett

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Abstract. Eukaryotic translation initiation factor 5A2(EIF5A2) has been demonstrated to be upregulated in numerous types of human cancer and is associated with cancer progression. However, the expression and role of EIF5A2 in non-small cell lung cancer (NSCLC) remains unclear. In the present study, the role of EIF5A2 in NSCLC was investigated, in addition to the underlying molecular mechanisms by which EIF5A2 acts. Relative EIF5A2 expression levels were determined in NSCLC cells and compared with levels in non-cancerous lung tissues. Short interfering (si)RNA targeted against EIF5A2 was used to knock down EIF5A2 levels in NSCLC cells. Cell proliferation, apoptosis rate, migration ability and invasion ability were determined in untreated and siRNA-treated NSCLC cells, in addition to the relative protein expression levels of various tumorigenic proteins and E-cadherin. EIF5A2 expression was significantly higher in NSCLC tissues compared with adjacent normal tissues. Knockdown of EIF5A2 in the NSCLC cells significantly inhibited cell proliferation and induced apoptosis. Furthermore, EIF5A2 silencing suppressed cell migratory and invasive capacities in vitro. Silencing of EIF5A2 in the NSCLC cells resulted in the downregulation of the tumorigenic proteins, apoptosis regulator Bcl-2 and myc proto-oncogene protein, and upregulation of E-cadherin, suggesting that EIF5A2 promotes proliferation and metastasis through these proteins. EIF5A2 may therefore serve as a novel therapeutic target for the treatment of NSCLC.

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The Role of Acetylation in the Subcellular Localization of an Oncogenic Isoform of Translation Factor eIF5A

Cited by 22 publications

References 15 publications

The translation factor eIF5A and human cancer

The translation factor eIF5A and human cancer

Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered?

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

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