The translation factor eIF5A and human cancer

Abstract

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.

Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels

“…As polyproline stretches facilitate protein-protein interactions relevant to a range of biological events including signal transduction and cytoskeletal remodeling (20,21), this raises the possibility that eIF5A has the capability to control cellular processes by modulating the expression of subsets of proteins with polyproline motifs. Emerging work supports this idea as eIF5A does not regulate general protein synthesis, but appears to have evolved to fine-tune the production of subsets of proteins in a contextual manner (22,23).…”

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

“…For the migration assay, H1299 and H460 cells (2x10 5 ) were resuspended in 100 µl serum-free RPMI medium and loaded into the upper chamber of a modified Boyden chamber (Neuro Probe, Inc., Gaithersburg, MD, USA). The lower chamber was filled with RPMI medium and vascular endothelial growth factor (50 ng/ml).…”

“…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. Downregulation of EIF5A2 prevents EMT in NSCLC (11), while overexpression of EIF5A2 is an adverse prognostic marker of survival for patients with stage I NSCLC (12).…”

“…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).…”

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

“…DDX4 is also subject to arginine methylation of unknown function. eIF5A eIF5A exists in two isoforms, the ubiquitously expressed eIF5A1 and the less-well characterized testis-and brainrestricted eIF5A2 [45,46]. eIF5A1 undergoes nucleocytoplasmic shuttling and its cytoplasmic functions, studied largely in yeast and non-mammalian vertebrates, include translation elongation and mRNA turnover.…”