Regulation of Polyamine Synthesis in Mammalian Cells

Persson, Lo; Holm, Ingvar; Stjernborg, Louise; Heby, Olle

doi:10.1007/978-1-4684-5637-0_24

Cited by 31 publications

(45 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AdoMet also interacts with folate metabolism and thus all the reactions involving folate (18,19). AdoMet is necessary for the synthesis of the essential polyamines spermidine and spermine (20,21). AdoMet is synthesized in a one-step condensation of methionine and ATP catalyzed by AdoMet synthetase (methionine ATP transferase, MAT, EC 2.5.1.6).…”

mentioning

confidence: 99%

Effect of Nicotine on Lung S-Adenosylmethionine and Development of Pneumocystis Pneumonia

Shivji

Burger

Moncada

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Because S-adenosylmethionine (AdoMet) is required by Pneumocystis carinii in vitro, Pneumocystis infection depletes plasma AdoMet of rats and humans, nicotine reduces AdoMet of guinea pig lungs, and smoking correlates with reduced episodes of Pneumocystis pneumonia (PCP) in AIDS patients, we tested the effect of nicotine treatment on PCP using a rat model. Intraperitoneal infusion of 400 g of R-(؉) nicotine kg ؊1 h ؊1 intraperitoneal for 21 days caused a 15-fold reduction in lung AdoMet although neither plasma nor liver were changed. Infusion of 4 and 400 g kg ؊1 h ؊1 into immunosuppressed rats, beginning when rats were inoculated with P. carinii, caused 85 and 99.88% reductions, respectively, in P. carinii cysts at sacrifice 21 days later; P. carinii nuclei were reduced by 91.2 and >99.99%, respectively. This effect was reversed by concomitant administration of AdoMet with nicotine. Treatment with AdoMet alone increased infection intensity. We conclude that AdoMet is a critical and limiting nutrient for Pneumocystis thus can serve as a therapeutic target for PCP. Regarding the mechanism, nicotine treatment caused no change in rat lung activity of AdoMet synthesizing methionine ATP transferase activity nor was there any evidence of increased AdoMet utilization for methylation reactions. Except of a doubling of putrescine, nicotine treatment also did not change lung polyamine content. However, key polyamine anabolic and catabolic enzymes were upregulated, and there were corresponding changes in polyamine metabolic intermediates. We conclude that chronic nicotine treatment increases lung polyamine catabolic/anabolic cycling and/or excretion leading to increased AdoMet-consuming polyamine biosynthesis and depletion of lung AdoMet.

show abstract

mentioning

confidence: 99%

Effect of Nicotine on Lung S-Adenosylmethionine and Development of Pneumocystis Pneumonia

Shivji

Burger

Moncada

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Although the induction of antizyme usually requires high concentrations of polyamines, it has also been achieved using 0.1 pM putrescine 1381. In addition to stimulating ODC degradation, polyamines appear to affect the synthesis of the enzyme as measured by pulse labeling with [3SS]methionine [16,17,[19][20][21]391. The conclusion that the feedback control of ODC synthesis is exerted at the level of translation is based on the finding that polyamine-mediated changes in the synthesis of ODC occur without any changes in the ODC mRNA level [16,17,[19][20][21]391.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to stimulating ODC degradation, polyamines appear to affect the synthesis of the enzyme as measured by pulse labeling with [3SS]methionine [16,17,[19][20][21]391. The conclusion that the feedback control of ODC synthesis is exerted at the level of translation is based on the finding that polyamine-mediated changes in the synthesis of ODC occur without any changes in the ODC mRNA level [16,17,[19][20][21]391. Since the rate of initiation is usually the rate-limiting step in protein synthesis an increase in the efficiency by which an mRNA is translated should be reflected in the mRNA being associated with larger polysomes, whereas a decrease in the efficiency of translation should be observed as fewer ribosomes binding to the mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, treatment with polyamine synthesis inhibitors causes a marked increase in cellular ODC content which cannot be explained by a change in the apparent turnover of the enzyme [13,14, 191. Using pulse radiolabeling with [35S]methionine, it has been shown that the incorporation of radioactivity into ODC is increased when the cellular levels of polyamines are low, and decreased when the cells are supplied with polyamines at micromolar concentrations in their growth medium [17,[19][20][21]. Assuming that the incorporation of methionine represents the synthesis of the enzyme, it appears that ODC is regulated by polyamines at the level of protein synthesis.…”

mentioning

confidence: 99%

“…Assuming that the incorporation of methionine represents the synthesis of the enzyme, it appears that ODC is regulated by polyamines at the level of protein synthesis. The steady-state level of ODC mRNA is not affected by the cellular supply of polyamines, indicating that regulation occurs at the translational level [16,17,[19][20][21][22].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Feedback regulation of mammalian ornithine decarboxylase

Lövkvist

Stjernborg

Persson

1993

European Journal of Biochemistry

Self Cite

View full text Add to dashboard Cite

Ornithine decarboxylase catalyzes the first step in the biosynthesis of polyamines in mammalian cells. The enzyme is subject to various control mechanisms to maintain adequate intracellular levels of polyamines. Polyamines exert a strong feedback control on ornithine decarboxylase. In a recent study [van Daalen Wetters, T., Macrae, M., Brabant, M., Sittler, A. & Coffino, P. (1989) Mol. Cell. Biol. 9, 5484-54901, it was concluded that feedback control of ornithine decarboxylase is mainly, if not exclusively, a posttranslational phenomenon. The existence of a fast-acting polyamine-stimulated component of ornithine decarboxylase degradation that acts on newly synthesized monomeric forms of the enzyme was postulated. In the present study we have used a transient expression system to test this hypothesis. The expression of ornithine decarboxylase in mock-transfected COS cells varied depending on the cellular supply of polyamines as has been found in other mammalian cells. Thus, supplementing the cells with exogenous spermidine resulted in a marked decrease in ornithine decarboxylase activity, whereas depletion of intracellular polyamines, using an ornithine decarboxylase inhibitor, gave a large increase in the cellular content of the enzyme. COS cells expressing an ornithine decarboxylase mRNA devoid of its 5' non-translated region did not exhibit any feedback control of the enzyme, neither in the presence of exogenous spennidine nor when the intracellular polyamine levels were depleted to the same extent as in the mock-transfected COS cells. The results strongly suggest that the feedback control of ornithine decarboxylase is not merely a posttranslational phenomenon.Cell proliferation is dependent on an adequate supply of the polyamines putrescine, spermidine and spennine [ 1 -31. The first step in the biosynthesis of polyamines is catalyzed by ornithine decarboxylase (ODC), which is regulated by a multitude of mechanisms [4]. Induction of cell growth is often accompanied by an increased transcription of the ODC gene. In many cases the increase in ODC mRNA is much less than the increase observed in ODC activity [5-91. This may partly be explained by a stabilization of the enzyme. However, part of the increase in ODC activity appears to be due to an increase in the efficiency of ODC mRNA translation. Since the turnover of ODC is among the fastest known for a mammalian enzyme [lo], any change in the synthesis or degradation of ODC will rapidly be manifested in a change in the enzyme activity [ll].Polyamines exert a strong feedback control on ODC. A decrease in cellular polyamine content will rapidly cause an increase in the amount of ODC regulation. It has been demonstrated that the turnover of ODC is stimulated when cells are exposed to an excess of extracellular polyamines [17, 181. However, to obtain this effect large quantities of polyamines, often at millimolar concentrations, have to be used. Nevertheless, ODC is downregulated by the addition of micromolar concentrations of polyamines to cells [14,16,17, 191....

show abstract