Antiretroviral Effects of Deoxyhypusyl Hydroxylase Inhibitors

Andrus, Linda; Szabo, Paul; Grady, Robert W.; Hanauske, Axel‐R.; Huima-Byron, Tellervo; Slowinska, Bozena; Zagulska, Sylwia; Hanauske-Abel, Hartmut M.

doi:10.1016/s0006-2952(98)00053-7

Cited by 61 publications

(68 citation statements)

References 71 publications

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“…The expression of functional eIF5A is also inhibited by mimosine treatment which generates an unmodified eIF5A lacking hypusine residue (Hanauske-Abel et al, 1994;Andrus et al, 1998). We found that mimosine treatment inhibits B50% of global protein synthesis (Dong and Zhang, 2003) while severe depletion of eIF5A resulted in an B30% decrease in the global protein synthesis (Kang and Hershey, 1994).…”

Section: Discussionmentioning

confidence: 80%

Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth

et al. 2004

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Translation initiation in eukaryotes is a rate-limiting step in protein synthesis. It is a complicated process that involves many eukaryotic initiation factors (eIFs). Altering the expression level or the function of eIFs may influence the synthesis of some proteins and consequently cause abnormal cell growth and malignant transformation. P170, the largest putative subunit of eIF3, has been found elevated in human breast, cervical, esophageal, and lung cancers, suggesting that p170 may have a potential role in malignant transformation and/or cell growth control. Our recent studies suggested that p170 is likely a translational regulator and it may mediate the effect of mimosine on the translation of a subset mRNAs. Mimosine, a plant nonprotein amino acid, inhibits mammalian DNA synthesis, an essential event of cell growth. The rate-limiting step in DNA synthesis is the conversion of the ribonucleotides to their corresponding deoxyribonucleotides catalysed by ribonucleotide reductase of which the activity is regulated by the level of its M2 subunit. It has been reported that inhibiting the activity of M2 also inhibits cell growth. To understand the relationship between protein and DNA synthesis and between p170 and cell growth control, we investigated in this study whether p170 regulates the synthesis of M2 and, thus, cell growth. We found that altering the expression level of p170 changes the synthesis rate of both M2 and DNA. Decreasing p170 expression in human lung cancer cell line H1299 and breast cancer cell line MCF7 significantly reversed their malignant growth phenotype. However, the overall [ 35 S]methionine incorporation following dramatic decrease in p170 expression was only B25% less than the control cells. These observations, together with our previous findings, suggest that p170 may regulate the translation of a subset mRNAs and its elevated expression level may be important for cancer cell growth and for maintaining their malignant phenotype.

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Section: Discussionmentioning

confidence: 80%

Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth

et al. 2004

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“…Furthermore, metal chelating inhibitors of DOHH, e.g. deferiprone and ciclopirox olamine, have been reported to inhibit replication of human immunodeficiency virus-1 (44). 4 Taken together, the ability to limit eIF5A hypusination may provide a useful tool for targeted control of cell growth and expansion in disease states.…”

Section: Discussionmentioning

confidence: 99%

Deoxyhypusine Hydroxylase Is an Fe(II)-dependent, Heat-repeat Enzyme

Kim

Kang

Wolff

et al. 2006

Journal of Biological Chemistry

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Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of hypusine (N -(4-amino-2-hy- 2؉ . The role of the strictly conserved His-Glu residues was evaluated by site-directed mutagenesis. Substitution of any single amino acid in the four His-Glu motifs with alanine abolished the enzyme activity. Of these eight alanine substitutions, six, including H56A, H89A, E90A, H207A, H240A, and E241A, caused a severe reduction in the iron content. Our results provide strong evidence that Fe(II) is the active-site-bound metal critical for DOHH catalysis and that the strictly conserved His-Glu motifs are essential for iron binding and catalysis. Furthermore, the iron to DOHH stoichiometry and dependence of iron binding on each of the four conserved His-Glu motifs suggest a binuclear iron mediated reaction mechanism, distinct from that of other Fe(II)-dependent protein hydroxylases, such as prolyl 4-hydroxylase or lysyl hydroxylases.

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“…It has been reported that mimosine has two functions as an iron chelator and as an inhibitor of deoxyhypusyl hydroxylase (DOHH) (Hanauske-Abel et al, 1994;Andrus et al, 1998), an enzyme responsible for the second step of synthesis of the unique amino acid, hypusine, in eIF5A. Hypusine is critical for eIF5A function and is formed by a two-step posttranslational modification: synthesis and hydroxylation of deoxyhypusine catalyzed by deoxyhypusine synthase (DHS) and DOHH, respectively (Park et al, 1993a).…”

Section: Mimosine Inhibits P170 Protein Synthesis By Its Iron-chelatimentioning

confidence: 99%

“…The hypusine residue of eIF5A is critical to its function (Park et al, 1993a,b). Mimosine is an inhibitor of DOHH, essential for hypusine formation, and consequently inhibits the formation of hypusine and thus the function of eIF5A (HanauskeAbel et al, 1994;Andrus et al, 1998), which has been reported to be critical for cell growth and survival (Schnier et al, 1991;Park et al, 1998). Interestingly, there was only 30% decrease in global protein synthesis in yeast with eIF5A depleted (Kang and Hershey, 1994).…”

Section: Control Of Protein Synthesis By Eif3 P170mentioning

confidence: 99%

EIF3 p170, a Mediator of Mimosine Effect on Protein Synthesis and Cell Cycle Progression

Dong

Zhang

2003

MBoC

114

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l-Mimosine, a plant amino acid, can reversibly block mammalian cells at late G1 phase and has been suggested to affect translation of mRNAs such as p27, the CDK inhibitor. However, the mechanism of this effect is not known. Regulation of translation generally occurs at the initiation step that, in mammalian cells, is a complex process that requires multiple eukaryotic initiation factors (eIFs) and ribosome. The effects of mimosine on initiation factors or regulators consequently will influence translation initiation. P170, a putative subunit of eIF3, has been suggested to be nonessential for eIF3 function to form preinitiation complexes and it may function as a regulator for translation of a subset of mRNAs. In this article, we tested this hypothesis and investigated whether eIF3 p170 mediates mimosine effect on mRNA translation. We found that p170 translation was dramatically reduced by mimosine due to its iron-chelating function. The decreased expression of p170 by mimosine caused diminished de novo synthesis of tyrosinated ␣-tubulin and elevated translation of p27 before cell cycle arrest. These observations suggest that p170 is likely an early response gene to mimosine treatment and a mediator for mimosine effect on mRNA translation. The effect of p170 on the synthesis of tyrosinated ␣-tubulin and p27 in a reciprocal manner also suggests that p170 functions as a regulator for mRNA translation. INTRODUCTIONl-Mimosine, a plant amino acid derived from seeds of Leucaena leucocephala or Mimosa pudica, can specifically and reversibly block mammalian cells at late G1 phase (Lalande, 1990;Mosca et al., 1992). Mimosine is commonly used as a synchronizing agent for investigating cell cycle progression in mammalian cells (Wang et al., 1995;Hughes and Cook, 1996). However, the molecular mechanism of mimosine action is ill-defined. It has been reported that the cells treated with mimosine lack proteins required for initiation and elongation of DNA replication (Kalejta and Hamlin, 1997). Although mimosine does not affect mRNA synthesis in general (Tsai and Ling, 1971), a subset of mRNAs was found to relocate to the mono-ribosome pool at the expense of polyribosome fraction after mimosine treatment. On mimosine removal, they reappeared in poly-ribosome pool, indicating that the mimosine effect is reversible (Hanauske-Abel et al., 1995). A recent study showed that expression of the cyclindependent kinase inhibitor p27 was elevated at the translational level by mimosine (Wang et al., 2000). These findings suggest that mimosine may modulate the synthesis of some proteins, which in turn causes inhibition of DNA replication and cell cycle arrest. One possible mechanism for such effect is that mimosine affects the synthesis and/or the function of proteins controlling mRNA translation.The rate-limiting step in mRNA translation is the initiation step. In eukaryotes, 11 factors have been identified that participate in the translation initiation step (Hershey and Merrick, 2000). Among these factors, eIF3 is the largest and the most ...

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Antiretroviral Effects of Deoxyhypusyl Hydroxylase Inhibitors

Cited by 61 publications

References 71 publications

Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth

Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth

Deoxyhypusine Hydroxylase Is an Fe(II)-dependent, Heat-repeat Enzyme

EIF3 p170, a Mediator of Mimosine Effect on Protein Synthesis and Cell Cycle Progression

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