The role of eIF5A in protein synthesis

Cell cycle (Georgetown, Tex.) (Impact Factor: 5.01). 11/2011; 10(21):3617-8. DOI: 10.4161/cc.10.21.17850
Source: PubMed
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    ABSTRACT: Cancer etiology is influenced by alterations in protein synthesis which are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a post-translational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells could be blocked by DOHH inhibition with either of these pharmacological agents, as well as by RNAi-mediated silencing of eIF5A, DOHH or other enzymes in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (HSP27, NM23 and DJ1) were downregulated at the translational level, whereas Group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations of Hsp27 control confirmed that eIF5A and DOHH were required for its expression in cervical cancer cells and for regulation of its key targets I?B and NF?B there. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone which might be repositioned to control cancer cell growth.
    Cancer Research 11/2013; 74(2). DOI:10.1158/0008-5472.CAN-13-0474 · 9.28 Impact Factor
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    ABSTRACT: Differential regulation of transcript stability is an effective means by which an organism can modulate gene expression. A well characterised example is glutamine signalled degradation of specific transcripts in Aspergillus nidulans. In the case of areA, which encodes a wide-domain transcription factor mediating nitrogen metabolite repression, the signal is mediated through a highly conserved region of the 3' UTR. Utilising this RNA sequence we isolated RrmA, an RNA recognition motif protein. Disruption of the respective gene led to loss of both glutamine signalled transcript degradation as well as nitrate signalled stabilization of niaD mRNA. However, nitrogen starvation was shown to act independently of RrmA in stabilizing certain transcripts. RrmA was also implicated in the regulation of arginine catabolism gene expression and the oxidative stress responses at the level of mRNA stability. ΔrrmA mutants are hypersensitive to oxidative stress. This phenotype correlates with destabilization of eifE and dhsA mRNA. eifE encodes eIF5A, a translation factor within which a conserved lysine is post-translationally modified to hypusine, a process requiring DhsA. Intriguingly, for specific transcripts RrmA mediates both stabilization and destabilization and the specificity of the signals transduced is transcript dependent, suggesting it acts in consort with other factors which differ between transcripts.
    Molecular Microbiology 07/2013; DOI:10.1111/mmi.12324 · 5.03 Impact Factor
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    ABSTRACT: The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, while the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a non-viral polyethylenimine (PEI)-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by siRNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study we show that SNS01-T is preferentially taken up by malignant B-cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.Molecular Therapy (2014); doi:10.1038/mt.2014.24.
    Molecular Therapy 02/2014; 22(9). DOI:10.1038/mt.2014.24 · 6.43 Impact Factor