The translation factor eIF5A and human cancer

Abstract

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. This article is part of a Special Issue entitled: Translation and Cancer.

Keywords: Cancer therapeutics; Eukaryotic initiation factor eIF5A; Hypusine modification; Protein synthesis; Translational control; Tumorigenesis.

Figure 1. eIF5A modification pathway and inhibitors

Deoxyhypusine synthase (DHS) catalyzes aminobutyl (blue ) transfer from spermidine to the ε-amino group of lysine-50 of human eIF5A (gray ) using NAD⁺ as cofactor, yielding deoxyhypusine (Dhp). Deoxyhypusine hydroxylase (DOHH) hydroxylates Dhp to hypusine (Hpu) in an Fe(II)-dependent reaction using molecular oxygen. The spermidine analog GC7 (N1-guanyl-1,7-diaminoheptane) inhibits DHS. The drugs ciclopirox (6-cyclohexyl-1-hydroxy-4-methyl-(1H)-pyrid-2-one) and deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) inhibit DOHH. (Modified from Hoque et al. [34]; reproduction permitted by BioMed Central.)

Figure 2. Model of eIF5A action during polypeptide chain elongation

In S. cerevisiae, eIF5A relieves ribosomal stalling at sequences containing consecutive proline residues (blue-circled P). The model depicts a ribosome stalled at a run of proline codons after condensing 2 proline residues in a nascent polypeptide chain and before the addition of a third proline. The peptidyl-tRNA is in the ribosomal P site and the next residue, on Pro-tRNA^Pro, is in the A site (left). eIF5A (brown) binds near the ribosomal E site with its hypusine side chain adjacent to the peptidyl-tRNA in the peptidyl transferase center of the ribosome where it can facilitate peptide bond formation (right). (Reprinted from Guttierez et al. [33] with permission from Elsevier.)

Figure 3. Putative eIF5A regulon

Hypusine-containing eIF5A is proposed to affect protein expression by enhancing the translation of Group 1 mRNAs (resulting in up-regulation), and the turnover of Group 2 mRNAs (resulting in down-regulation). The targets may be direct or secondary to eIF5A's biochemical action, are collectively considered the eIF5A regulon, and influence tumorigenesis and related cellular processes. (Reproduced from Mémin et al. [23] as permitted by AACR.)