Cytosolic and nuclear spermidine acetyltransferases in growing NIH 3T3 fibroblasts stimulated with serum or polyamines: relationship to polyamine-biosynthetic decarboxylases and histone acetyltransferase

Desiderio, Maria Alfonsina; Mattei, Stefano; Biondi, G.; Colombo, Monika

doi:10.1042/bj2930475

Cited by 24 publications

(12 citation statements)

References 45 publications

(72 reference statements)

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“…Cells were seeded at a concentration of 20 000 cells ml-' and, after at least two doubling times, 100 gM MAP and 25 jiM AbeAdo were added to the culture medium for 72 h. The concentrations of MaP and AbeAdo were selected on the basis of previous work (Desiderio et al, 1993).…”

Section: Polyamine Inhibitor Treatmentmentioning

confidence: 99%

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Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Desiderio

Bergamaschi²,

Mascellani³

et al. 1997

Br J Cancer

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Summary Inhibitors of ornithine decarboxylase (ODC), such as a-difluoromethylornithine (DFMO), may influence the cytotoxicity of anti-tumour agents that interact with DNA. Intracellular levels of putrescine and spermidine were markedly reduced by ODC inhibitors while the level of spermine, which is the main polyamine in nuclei, was unchanged. By combining a novel inhibitor of ODC, such as (2R, 5R)-6-heptyne-2,5-diamine (MDL 72.175, MAP), with an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), such as 5'-{[(Z)-4-aminobut-2-enyl]methylamino}-5'-deoxyadenosine (MDL 73.81 1, AbeAdo), spermine was selectively depleted in a human ovarian cancer cell line OVCAR-3 (i.e. spermine became almost undetectable whereas the levels of spermidine and putrescine were not affected). The . The addition of spermine before drug treatment restored the sensitivity to the DNA topoisomerase 11 inhibitors, thus indicating that the reduced effect was related to the intracellular spermine level. The reason for the reduction in cytotoxicity is unclear, but it does not appear to be related to a cell cycle effect or to a decrease in the intracellular level of DNA topoisomerase 11. Drugs that modify polyamine biosynthesis are under early clinical development as potential new anti-tumour agents. These findings illustrate the need for caution in combining such drugs with DNA topoisomerase 11 inhibitors.

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Section: Polyamine Inhibitor Treatmentmentioning

confidence: 99%

“…The combination of specific inhibitors of ODC and SAMDC can block polyamine biosynthesis, causing a remarkable drop in spermine levels (Desiderio et al, 1993). This result cannot be obtained with any ODC inhibitor used alone (Pegg, 1988).…”

mentioning

confidence: 99%

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Desiderio

Bergamaschi²,

Mascellani³

et al. 1997

Br J Cancer

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“…36 Samples of 10 1 10 6 cells were sonicated glutamine, 50 IU penicillin/mL, 50 mg streptomycin/mL, and 10% with 60 mL of 25 mmol/L Tris/HCl, pH 7.2, containing 0.1 mmol/L horse serum, at 37ЊC in a 5% CO 2 atmosphere. Horse serum was ethylenediaminetetraacetic acid and 2 mmol/L dithiothreitol and used because it contains very low activity of amine oxidases that were centrifuged at 14,000 rpm for 20 minutes in an Eppendorf mimight oxidize AbeAdo and higher polyamines with formation of toxic crocentrifuge at 4ЊC.…”

Section: -{[(Z)-4-aminobut-2-enyl]methylamino}-5-deoxyadenosinementioning

confidence: 99%

“…mmol/L) 27 or of the combination of MAP (100 mmol/L) plus AbeAdo Protein Content. The protein content of the acid-precipitable frac-(25 mmol/L) 36 was studied, the inhibitors were dissolved in the com-tion of the samples used for high-pressure liquid chromatography plete culture medium, and if necessary, the pH was adjusted before assay and of cell extracts used for ODC assay were measured using the medium was dispensed in each flask. When the effect of putresthe method described by Lowry et al 49 cine was tested, a concentrated polyamine solution was prepared Statistical Analysis.…”

Section: -{[(Z)-4-aminobut-2-enyl]methylamino}-5-deoxyadenosinementioning

confidence: 99%

Effects of Polyamine Imbalance on the Induction of Stress Genes in Hepatocarcinoma Cells Exposed to Heat Shock

et al. 1996

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called ''heat shock proteins'' (hsps). [4][5][6][7][8][9] Not only the response to The expression of hsp70-the inducible member of the temperature is conserved but the heat-inducible proteins are corresponding heat shock gene family-of the oxidative conserved as well; among them, the hsp70 family of hsps are stress marker gene heme oxygenase (HOx), and of the particularly important for amount, constancy of induction, immediate early response genes c-fos and c-jun has been and possible role as cellular thermometer regulating the exstudied in FAO hepatocarcinoma cells depleted of polypression of all hsps. [10][11][12] Heat shock has additional effects on amines and exposed to heat shock. Depletion of polymessenger RNA (mRNA) stability and translational control, amines was obtained in short-term experiments (24-48 which contribute to the preferential expression of hsps. Behours) by the use of a-difluoromethylornithine (DFMO), cause of their rapid induction, most of the studies on hsps a classical inhibitor of ornithine decarboxylase (ODC), have emphasized this characteristic response to heat but or of the combination of the newly available inhibitors of ODC and S-adenosylmethionine decarboxylase, i.e., many hsps are also constitutively expressed. The main func-(2R,5R)-hept-6-yne-2,5-diamine (MAP) and 5-{[(Z)-4-tion of constitutive and inducible hsps is to regulate the foldaminobut-2-enyl]methylamino}-5-deoxyadeno-sine (Ab-ing of newly synthesized protein and to help in their refolding eAdo). Under our experimental conditions polyamine im-during or after cell injury. 8,9 balance was realized without appreciable growth arrestIn addition to exposure to heat, other noxious agents, conand impaired expression of growth-related genes. De-nected in some way with protein malfolding or denaturation, creases of putrescine and spermidine 48 hours after can induce the synthesis of hsps 13 and may also be relevant DFMO prevented the induction of hsp70 messenger RNA to liver cell pathology.14,15 Indeed, it has been recognized that (mRNA), whereas depletion of spermidine and spermine ''the heat-shock response is for hepatologists, too '' 16 and that obtained with MAP/AbeAdo decreased intensity and du-the application of hsps to clinical medicine is on the horiration of post-heat shock accumulation of hsp70 mRNA. zon. 17,18 The induction of hsp70 mRNA starts with the activaInductions of HOx, c-jun and c-fos were also inhibited. tion of the heat shock transcription factor (HSF), which binds Because MAP/AbeAdo caused also an intracellullar accu-to the consensus sequence heat shock element (HSE) present mulation of putrescine, we tested the effect of exogenous in the promoter of heat shock genes and transactivates the putrescine, which was found to stabilize the mRNAs for gene. In some circumstances, however, the binding is not hsp70 and c-jun. Hsp70 and HOx are thought to play a followed by the appearance of hsp70 mRNA, 19,20 which argues protective role, and the proteins of c-jun and c-fos consti-for the need of permissive conditio...

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“…In addition to the cytoplasmic polyamine acetyltransferase, mammalian cells also have a nuclear enzyme of unclear function that acetylates the N 8 -amino group of spermidine 7 . Acetylation of spermidine to N 8 -acetylspermidine was first reported with the identification of a nuclear acetyltransferase, highly related to HATs 8 , providing an intriguing link between spermidine metabolism and histone acetylation [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

P/CAF-mediated spermidine acetylation regulates histone acetyltransferase activity

Burgio

Corona

Nicotra

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Histones and polyamines are important determinants of the chromatin structure. Histones form the core of nucleosome particles and their modification by acetylation of N-terminal tails is involved in chromatin structural changes and transcriptional regulation. Polyamines, including spermidine, are also targets of both cytoplasmic and nuclear acetylation, which in turn alters their affinity for DNA and nucleosomes. Previous studies report the interplay between polyamines metabolism and levels of histone acetylation, but the molecular basis of this effect is still unclear. In this work, we have analyzed the in vitro effect of spermidine on histone H3 acetylation catalyzed by P/CAF, a highly conserved histone acetyltransferase (HAT) (E.C. 2.3.1.48). We have observed that spermidine at very low concentrations activates P/CAF, while it has an inhibitory effect at concentrations higher than 4 mM. In addition, the in vitro bimodal effect of spermidine on histone H3 acetylation was also distinctly observed in vivo on polytene chromosomes of Drosophila melanogaster. We also performed kinetic studies indicating that the activating effect of low spermidine concentrations on P/CAF-HAT activity is based on its involvement as a substrate for P/CAF to produce N 8 -acetylspermidine that is able in turn to increase the enzyme activity up to four fold.

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Cytosolic and nuclear spermidine acetyltransferases in growing NIH 3T3 fibroblasts stimulated with serum or polyamines: relationship to polyamine-biosynthetic decarboxylases and histone acetyltransferase

Cited by 24 publications

References 45 publications

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Effects of Polyamine Imbalance on the Induction of Stress Genes in Hepatocarcinoma Cells Exposed to Heat Shock

P/CAF-mediated spermidine acetylation regulates histone acetyltransferase activity

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