The role of eukaryotic initiation factor 5A in the control of cell proliferation and apoptosis

Caraglia, Michele; Marra, Manuela; Giuberti, Gaia; D'Alessandro, Antonella; Budillon, Alfredo; Prete, Salvatore Del; Lentini, Alessandro; Beninati, Simone; Abbruzzese, Alberto

doi:10.1007/s007260170050

Cited by 70 publications

(61 citation statements)

References 66 publications

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“…At the same time the mutant showed initial signs of DNA fragmentation and activation of caspases, which are diagnostic markers of apoptotic death (35,55). Other researchers have also demonstrated the involvement of eIF5A in the apoptotic processes (56,57). The induction of apoptosis is often linked to the control of the cell cycle and the DNA damage checkpoint.…”

Section: Discussionmentioning

confidence: 99%

Temperature-sensitive eIF5A Mutant Accumulates Transcripts Targeted to the Nonsense-mediated Decay Pathway

Schräder

Young

Kozian

et al. 2006

Journal of Biological Chemistry

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The highly conserved protein eIF5A found in Archaea and all eukaryotes uniquely contains the posttranslationally formed amino acid hypusine. Despite being essential the functions of this protein and its modification remain unclear. To gain more insight into these functions temperature-sensitive mutants of the human EIF5A1 were characterized in the yeast Saccharomyces cerevisiae. Expression of the point mutated form V81G in a ⌬eIF5A strain of yeast led to a strongly temperature-sensitive phenotype and to a significantly reduced protein level at restrictive temperature. The mutant showed accumulation of a subset of mRNAs that was also observed in nonsense-mediated decay (NMD)-deficient yeast strains. After short incubation at restrictive temperature the mutant exhibited increased half-lives of the intron containing CYH2 pre-mRNA and mature transcripts of NMD-dependent genes. Reduced telomere silencing and shortening was detected in the V81G mutant further supporting similarities to NMD-deficient strains. Our data suggest that eIF5A mediates important cellular processes like cell viability and senescence through its effects on the stability of certain mRNAs.The cellular physiology of mRNA processing, transport, localization, and turnover is central to the process of gene expression at the posttranscriptional level. Increasing evidence has been found for a close connection between mRNA degradation processes and the steps of translation. The highly conserved hypusine-containing protein eIF5A has been implicated in both of these aspects of RNA metabolism; however, its precise cellular function is not yet fully understood.Hypusine formation is a two-step enzymatic reaction catalyzed by deoxyhypusine synthase and then deoxyhypusine hydroxylase (1). The disruption of genes encoding either eIF5A or deoxyhypusine synthase in yeast leads to a lethal phenotype (2) demonstrating that the deoxyhypusine residue is essential for the function of eIF5A and thus for proliferation and cell survival. The genome of Saccharomyces cerevisiae contains two HYP genes (HYP1, alias TIF51B or ANB1, and HYP2, alias TIF51A) coding for eIF5A. These genes are differentially expressed under aerobic and anaerobic conditions (3) and share an identity of 90%. HYP genes of other higher eukaryotes, e.g. one of the two human HYP genes (encoding EIF5A1), can functionally replace these yeast-specific genes (4, 5).The eIF5A protein was first isolated from rabbit reticulocyte lysate ribosomes and classified as a translation initiation factor because in vitro the protein enhanced the building reaction of the first peptide bond measured as the yield of methioninepuromycin (6). However, cell fractionation revealed that only a small fraction of the protein associated with ribosomes (7). Moreover depletion or inactivation of the protein in S. cerevisiae reduced the global protein synthesis rate by only 30% (8, 9). Thus, the role of eIF5A as a translation initiation factor remains to be confirmed.eIF5A is an RNA-binding protein (10), and it was hypothesized to re...

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Section: Discussionmentioning

confidence: 99%

Temperature-sensitive eIF5A Mutant Accumulates Transcripts Targeted to the Nonsense-mediated Decay Pathway

Schräder

Young

Kozian

et al. 2006

Journal of Biological Chemistry

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“…The expression of various members of the hnRNP family was found to be altered in lung cancer (47). Three other molecular targets listed in Table 2 are eukaryotic initiation factor 4A (eIF4A), an RNA helicase and a downstream regulator in the mammalian target of rapamycin signaling pathway (48), another initiation factor, eIF5A, and a translation elongation factor, eEF1A-1, implicated in signal transduction, cell proliferation, and apoptosis (49,50). The expression of all three translation factors in the HCT-116 cell line increased after treatment with celecoxib.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling Identifies Cyclooxygenase-2-Independent Global Proteomic Changes by Celecoxib in Colorectal Cancer Cells

Lou

Xiao²,

Stauffer³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Celecoxib, a selective inhibitor of the enzyme cyclooxygenase-2 (COX-2), has been shown to be a promising chemoprevention agent. The chemopreventive efficacy of celecoxib is believed to be a consequence of its COX-2-dependent and COX-2-independent effects on a variety of cellular processes including proliferation, apoptosis, angiogenesis, and immunosurveillance. In an attempt to identify proteomic markers modulated by celecoxib that are independent of its inhibitory effect on COX-2, the colorectal cancer cell line HCT-116, a nonexpresser of COX-2, was treated with celecoxib. We used the powerful, state-of-the-art two-dimensional difference gel electrophoresis technology coupled with mass spectrometric sequencing to compare global proteomic profiles of HCT-116 cells before and after treatment with celecoxib. Among the differentially expressed proteins identified following celecoxib treatment were proteins involved in diverse cellular functions including glycolysis, protein biosynthesis, DNA synthesis, mRNA processing, protein folding, phosphorylation, redox regulation, and molecular chaperon activities. Our study presents a comprehensive analysis of large-scale celecoxib-modulated proteomic alterations, at least some of which may be mechanistically related to the COX-2-independent chemopreventive effect of celecoxib. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1598 -606)

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“…Since depletion of eIF5A in yeast also causes an increase of G1-arrested cells, judged by cell morphology, it was proposed that eIF5A may be important for translating mRNAs encoding proteins required for cell cycle progression (Kang and Hershey 1994). This connection between eIF5A and cell cycle progression is further supported by the observation that blocking any step of hypusination, its essential post-translational modification, in mammalian cells inhibits cell proliferation (Park et al 1997), placing eIF5A among the potential targets for cancer therapy (Caraglia et al 2001).…”

mentioning

confidence: 88%

Pkc1 Acts Through Zds1 and Gic1 to Suppress Growth and Cell Polarity Defects of a Yeast eIF5A Mutant

Zanelli

Valentini

2005

Genetics

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eIF5A is a highly conserved putative eukaryotic translation initiation factor that has been implicated in translation initiation, nucleocytoplasmic transport, mRNA decay, and cell proliferation, but with no precise function assigned so far. We have previously shown that high-copy PKC1 suppresses the phenotype of tif51A-1, a temperature-sensitive mutant of eIF5A in S. cerevisiae. Here, in an attempt to further understand how Pkc1 functionally interacts with eIF-5A, it was determined that PKC1 suppression of tif51A-1 is independent of the cell integrity MAP kinase cascade. Furthermore, two new suppressor genes, ZDS1 and GIC1, were identified. We demonstrated that ZDS1 and ZDS2 are necessary for PKC1, but not for GIC1 suppression. Moreover, high-copy GIC1 also suppresses the growth defect of a PKC1 mutant (stt1), suggesting the existence of a Pkc1-Zds1-Gic1 pathway. Consistent with the function of Gic1 in actin organization, the tif51A-1 strain shows an actin polarity defect that is partially recovered by overexpression of Pkc1 and Zds1 as well as Gic1. Additionally, PCL1 and BNI1, important regulators of yeast cell polarity, also suppress tif51A-1 temperature sensitivity. Taken together, these data strongly support the correlated involvement of Pkc1 and eIF5A in establishing actin polarity, which is essential for bud formation and G1/S transition in S. cerevisiae.

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The role of eukaryotic initiation factor 5A in the control of cell proliferation and apoptosis

Cited by 70 publications

References 66 publications

Temperature-sensitive eIF5A Mutant Accumulates Transcripts Targeted to the Nonsense-mediated Decay Pathway

Temperature-sensitive eIF5A Mutant Accumulates Transcripts Targeted to the Nonsense-mediated Decay Pathway

Proteomic Profiling Identifies Cyclooxygenase-2-Independent Global Proteomic Changes by Celecoxib in Colorectal Cancer Cells

Pkc1 Acts Through Zds1 and Gic1 to Suppress Growth and Cell Polarity Defects of a Yeast eIF5A Mutant

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