Inhibition of cell growth through inactivation of eukaryotic translation initiation factor 5A (eIF5A) by deoxyspergualin

Nishimura, Kazuhiro; Ohki, Yuji; Shimogori, Tomomi; Sakata, Kumiko; Saiga, Kan; Beppu, Takanobu; Shirahata, Akira; Kashiwagi, Keiko; Igarashi, Kazuei

doi:10.1042/0264-6021:3630761

Cited by 23 publications

(18 citation statements)

References 39 publications

(37 reference statements)

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“…To distinguish between these two options, we kept DFMO in the culture medium after the overlay of control cells to prevent polyamine synthesis (Figure 5C). Because control cells treated with DFMO generally continue dividing for at least 2 d in vitro (Nishimura et al , 2002), they have enough polyamines to trigger cell division of polyamine-depleted cells, and, indeed, we observed that the regrowth of polyamine-depleted cells was again detected (Figure 5C), although DFMO reduced the proportion of BrdU-positive cells of DFMO/APCHA-treated cells.…”

Section: Impaired Microtubule Dynamics and Maintenance Of Gap Junctiomentioning

confidence: 58%

An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

Desforges

Curmi

Bounedjah

et al. 2013

MBoC

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Section: Impaired Microtubule Dynamics and Maintenance Of Gap Junctiomentioning

confidence: 58%

An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

Desforges

Curmi

Bounedjah

et al. 2013

MBoC

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“…3B), suggesting that DSG does not compromise the growth of the malaria parasite through inhibition of polyamine biosynthesis. DSG has earlier been demonstrated to inhibit formation of active eIF5A, which is generated by modification with hypusine, a derivative of spermidine, in mouse mammary carcinoma FM3A cells (40). However, the amount of hypusinated eIF5A in the malaria parasite was reduced only upon polyamine depletion at high micromolar concentrations of DSG (Fig.…”

Section: Effect Of Dsg On Polyamine Biosynthesis and Transport-mentioning

confidence: 90%

15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum

Ramya

Karmodiya

Surolia

et al. 2007

Journal of Biological Chemistry

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15-Deoxyspergualin, an immunosuppressant with tumoricidal and antimalarial properties, has been implicated in the inhibition of a diverse array of cellular processes including polyamine synthesis and protein synthesis. Endeavoring to identify the mechanism of antimalarial action of this molecule, we examined its effect on Plasmodium falciparum protein synthesis, polyamine biosynthesis, and transport. 15-Deoxyspergualin stalled protein synthesis in P. falciparum through Hsp70 sequestration and subsequent phosphorylation of the eukaryotic initiation factor eIF2␣. However, protein synthesis inhibition as well as polyamine depletion were invoked only by high micromolar concentrations of 15-deoxyspergualin, in contrast to the submicromolar concentrations sufficient to inhibit parasite growth. Further investigations demonstrated that 15-deoxyspergualin in the malaria parasite primarily targets the hitherto underexplored process of trafficking of nucleus-encoded proteins to the apicoplast. Our finding that 15-deoxyspergualin kills the malaria parasite by interfering with targeting of nucleus-encoded proteins to the apicoplast not only exposes a chink in the armor of the malaria parasite, but also reveals new realms in our endeavors to study this intriguing biological process. 15-Deoxyspergualin (DSG)4 ( Fig. 1), an analog of spergualin isolated from the culture broth of Bacillus laterosporus, inhibits the growth of the malaria parasite, Plasmodium, in vitro and in vivo, presumably by depleting its polyamine reserves (1, 2). However, other known inhibitors of polyamine biosynthesis, methylglyoxal-bis-(guanylhydrazone) analog (MGBCP), irinotecan hydrochloride (CPT11), and ␣-difluoromethyl ornithine (DFMO) are known to be incapable of suppressing malaria in infected mice (2). This led us to question the speculated mechanism of antimalarial action of DSG.Despite the uncertainty in the actual mechanism of action of DSG, DSG is known to bind cellular chaperones, Hsp70 and Hsp90, potently, via their regulatory C-terminal motif EEVD (3, 4). DSG does not inhibit their chaperone activity (3-5). However, it selectively enhances the ATPase activity of heat shock proteins that have the C-terminal EEVD motif, and this could be the basis of a specific modulation of the function of proteins that bind the EEVD motif of heat shock proteins (5).One of the cellular milieus in which heat shock proteins are speculated to be involved is translational regulation. Translation of an mRNA requires the formation of a ternary complex of the methionyl-tRNA, the mRNA and the 40 S subunit of the ribosome, a feat achieved through the intervention of the GTPbound form of the initiation factor eIF2 (6). Phosphorylation of eIF2␣ at Ser 51 blocks protein synthesis by preventing eIF2 recycling and depleting the cell of its pool of eIF2-GTP required for translation initiation (7). Several conditions of cellular stress trigger the phosphorylation of eIF2␣ via the activation of four different eIF2␣ kinases: PERK (PKR-like endoplasmic reticulum-associated kina...

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“…tion promoting greater vascularization around the cancer lesion and has also been found to protect cells from DNA-damaging agents and related apoptosis (Jeung et al, 2006). EIF5A1 (eukaryotic translation factor 1) has been shown to be involved in cell proliferation through the action of polyamines (Nishimura et al, 2002(Nishimura et al, , 2005, and plays a role in the regulation of TP53-related apoptosis (Li et al, 2004). PP1201, also known as transmembrane Bax inhibitor motif-containing 1 (TMBIM1), is a novel gene of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: Serial analysis of gene expression

Razvi

Peng

Dar

et al. 2007

Genes Chromosomes & Cancer

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Serial analysis of gene expression (SAGE) provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define gene expression alterations in Barrett's-related adenocarcinomas (BA), we produced eight SAGE libraries and obtained a total of 457,894 expressed tags with 32,035 (6.9%) accounting for singleton tags. The tumor samples produced an average of 71,804 tags per library, whereas normal samples produced an average of 42,669 tags per library. Our libraries contained 67,200 unique tags representing 16,040 known gene symbols. Five hundred and sixty-eight unique tags were differentially expressed between BAs and normal tissue samples (at least twofold; P

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Inhibition of cell growth through inactivation of eukaryotic translation initiation factor 5A (eIF5A) by deoxyspergualin

Cited by 23 publications

References 39 publications

An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum

Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: Serial analysis of gene expression

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