Molecular genetics of polyamine synthesis in eukaryotic cells

Heby, Olle; Persson, Lo

doi:10.1016/0968-0004(90)90216-x

Cited by 498 publications

(307 citation statements)

References 19 publications

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“…This fact strongly supports the idea previously suggested by several authors that parasites with an ODC of high turnover are tolerant to DFMO because they always contain a fraction of newly synthesized and active enzyme [30] su¤cient to produce small amounts of putrescine rapidly converted into spermidine (and eventually into trypanothione), which can support protozoan proliferation.…”

Section: Intracellular Pools Of Polyaminessupporting

confidence: 90%

Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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Trypanosomatid parasites containing a metabolically unstable ornithine decarboxylase (ODC) are naturally resistant to high levels of K K-difluoromethylornithine (DFMO) because this ODC inhibitor, though causing a drastic reduction of intracellular putrescine, elicits only a moderate decrease of the spermidine endogenous pool. In this study we have used a combination of DFMO with cyclohexylamine (CHA ; biscyclohexylammonium sulfate), an inhibitor of spermidine synthase, to reach a more complete depletion of spermidine. Under these conditions we have observed the arrest of proliferation not only in trypanosomatids with stable ODC but also in parasites with an enzyme of high turnover rate. In all cases the reinitiation of proliferation occurred only after the addition of exogenous spermidine, and neither putrescine nor spermine were able to induce the same effect. ß

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Section: Intracellular Pools Of Polyaminessupporting

confidence: 90%

Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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“…The biosynthesis of the naturally occurring polyamines, spermidine and spermine, is tightly regulated by a variety of mechanisms (Heby & Persson, 1990;Morris, 1991;Grillo & Colombatto, 1994;Shantz & Pegg, 1999)+ Fine control of intracellular polyamine levels is necessary, because overproduction of these compounds can lead to cellular toxicity and oncogenic transformation (Heby & Persson, 1990;Morris, 1991), whereas polyamine depletion inhibits cell growth (Pegg, 1988;Marton & Pegg, 1995)+ S-Adenosylmethionine decarboxylase (AdoMetDC) is one of the regulated enzymes in the pathway of polyamine biosynthesis+ Translation of mammalian AdoMetDC is controlled by the intracellular level of polyamines (White et al+, 1990) through a unique mechanism+ The mammalian AdoMetDC mRNA contains within its leader sequence a small open reading frame that encodes a peptide of sequence MAGDIS (Hill & Morris, 1992)+ This upstream open reading frame (uORF) suppresses translation of associated downstream cistrons through a mechanism that requires specific structural features in the carboxy-terminus of the encoded peptide (Hill & Morris, 1993;Mize et al+, 1998)+ The stringent requirements of the peptide structure implies that it interacts with a specific cellular target and, furthermore, this target seems to be conserved across species from mammals to yeast (Mize et al+, 1998)+ Intracellular polyamine levels in mammalian cells regulate the suppressive activity of the AdoMetDC uORF through a mechanism that involves modulation of the interaction of MAGDIS with its target (Ruan et al+, 1996)+ Although the mammalian uORF suppresses translation in yeast (Mize et al+, 1998), it has not been established whether this activity is regulated by polyamines+ In Saccharomyces cerevisiae, the level of the first enzyme of the polyamine pathway, ornithine decarboxy-lase (ODC) is feedback controlled by cellular polyamine content through a posttranslational mechanism (Fonzi, 1989) that involves regulated degradation by the proteasome (Toth & Coffino, 1999)+ Although the pattern of regulation of yeast ODC is similar to that found in mammalian cells, it is not known whether AdoMetDC is under translational control in yeast as it is in mammals+ In the present study, we find that the yeast SPE2 gene, which encodes AdoMetDC, does not have an associated uORF+ Additionally, ribosome loading on SPE2 mRNA is not enhanced by lowering cellular polyamine levels+ The mammalian AdoMetDC uORF was placed upstream of a reporter gene and introduced into a polyamine auxotroph of yeast+ Translation of mRNA generated from this construct was regulated by the uORF in a manner identical to that observed in mammalian cells+ Polyamine depletion of the cells enhanced both translational efficiency and density o...…”

Section: Introductionmentioning

confidence: 99%

A mammalian sequence-dependent upstream open reading frame mediates polyamine-regulated translation in yeast

Mize

Morris

2001

RNA

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In mammals, control of S-adenosylmethionine decarboxylase (AdoMetDC) translation is one component of a feedback network that regulates intracellular levels of the polyamines, spermidine, and spermine. AdoMetDC mRNA from mammals contains a highly conserved upstream open reading frame (uORF) within its leader sequence that confers polyamine-regulated suppression of translation on the associated downstream cistron. This regulation is mediated through an interaction that depends on the amino acid sequence of the uORF-encoded hexapeptide. It remains to be shown whether polyamines participate directly in this interaction or indirectly through a specialized signal transduction pathway. We show that Saccharomyces cerevisiae does not have a uORF associated with its AdoMetDC gene (SPE2) and that ribosome loading on the SPE2 mRNA is not positively influenced by polyamine depletion, as it is in mammalian cells. Nevertheless, the mammalian AdoMetDC uORF, when introduced into a polyamine auxotroph of yeast, conferred polyamine regulation of both translational efficiency and ribosome loading on the associated mRNA. This regulatory activity depended on the amino acid sequence encoded by the fourth and fifth codons of the uORF, as in mammalian cells. The fact that the regulatory properties of this mammalian translational control element are quite similar in both mammalian and yeast cells suggests that a specialized signal transduction pathway is not required. Rather, it seems likely that polyamines may be directly participating in an interaction between the uORFencoded peptide and a constitutive component of the translation machinery, which leads to inhibition of ribosome activity.

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“…These results, although unexpected, could indicate that under 24-h serumdeprived conditions, most of HTC-IR cells were rather in G 1 than in G 0 phase of the cell cycle. It is known that ODC induction and putrescine accumulation occur in G 1 and G 2 phases of the cell cycle, whereas spermine and spermidine accumulate in S phase along with RNA and DNA synthesis (Heby and Persson, 1990). Treatment with celecoxib produced dramatic decrease in ODC activity.…”

Section: Discussionmentioning

confidence: 98%

Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

et al. 2003

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Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose-and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.

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Molecular genetics of polyamine synthesis in eukaryotic cells

Cited by 498 publications

References 19 publications

Spermidine is essential for normal proliferation of trypanosomatid protozoa

Spermidine is essential for normal proliferation of trypanosomatid protozoa

A mammalian sequence-dependent upstream open reading frame mediates polyamine-regulated translation in yeast

Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

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