Impairment of DNA Replication within One Cell Cycle after Seeding of Cells in the Presence of a Polyamine‐Biosynthesis Inhibitor

Fredlund, Jan O.; Oredsson, Stina

doi:10.1111/j.1432-1033.1996.0539p.x

Cited by 23 publications

(14 citation statements)

References 28 publications

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“…The G 2 /M progression appeared not to be affected, as evaluated by following the movement of BrdUrd-labelled cells into G 1 of the following cell cycle. These results are similar to those found after treating CHO cells with DFMO [16] and CGP 48664 [21]. As the G 1 /S phase transition (i.e.…”

Section: Discussionsupporting

confidence: 89%

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Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle

Alm

Berntsson

Kramer

et al. 2000

European Journal of Biochemistry

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When Chinese hamster ovary cells were seeded in the presence of the spermine analog N 1 ,N 11 -diethylnorspermine (DENSPM), cell proliferation ceased; this was clearly apparent by cell counting 2 days after seeding the cells. However, 1 day after seeding there was a slight difference in cell number between control and DENSPM-treated cultures. To investigate the reason for this easily surpassed slight difference, we used a sensitive bromodeoxyuridine/flow cytometry method. Cell cycle kinetics were studied during the first cell cycle after seeding cells in the absence or presence of DENSPM. Our results show that DENSPM treatment did not affect the progression of the cells through G 1 or the first G 1 /S transition that took place after seeding the cells. The first cell cycle effect was a delay in S phase as shown by an increase in the DNA synthesis time. The following G 2 /M transition was not affected by DENSPM treatment. DENSPM treatment inhibited the transient increases in putrescine, spermidine, and spermine pools that took place within 24 h after seeding. Thus, in conclusion, the first cell cycle phase affected by the inhibition of polyamine biosynthesis caused by DENSPM was the S phase. Prolongation of the other cell cycle phases occurred at later time points, and the G 1 phase was affected before the G 2 /M phase.Keywords: bromodeoxyuridine; cell cycle; polyamines; polyamine analog; S phase.The cationic polyamines, putrescine, spermidine and spermine, are constitutive intracellular components. They are synthesized in well-regulated biochemical reactions. Studies using different polyamine biosynthesis inhibitors and analogs have shown that polyamines are necessary for normal cell growth and development [1±4]. Polyamine-deficient cells cease to proliferate. In general, the inhibition of cell proliferation is not apparent as a decrease in cell number until after one or two cell cycles. Thus, many studies trying to elucidate the role of polyamines in cell proliferation using inhibitors have been performed only after an apparent difference in cell number between control and inhibitor treated cells has been found. However, using a sensitive method to investigate cell cycle kinetics, we have found that cell cycle progression is perturbed in polyaminedeficient cells before there is an obvious decrease in cell number. The cause of this is that mammalian cells have long cell cycle times and, although the cell cycle phase distribution may be the same in percentage, the actual distribution of cells in the various cell cycle phases may be quite different.As Kramer et al.[5] reports, the requirements for polyamines in cell cycle progression have been investigated in a number of studies and variable results have been obtained: effects on the G 1 /S transition [6±11], the S and/or the G 2 phase [12±16], and all cell cycle phases [17]. A number of causes for the variability are mentioned, e.g. difference in cell type being studied, the enzyme being inhibited, and/or the specific inhibitor being used. Another important facto...

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Section: Discussionsupporting

confidence: 89%

“…As Kramer et al . [5] reports, the requirements for polyamines in cell cycle progression have been investigated in a number of studies and variable results have been obtained: effects on the G 1 /S transition [6–11], the S and/or the G 2 phase [12–16], and all cell cycle phases [17]. A number of causes for the variability are mentioned, e.g.…”

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confidence: 99%

Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle

Alm

Berntsson

Kramer

et al. 2000

European Journal of Biochemistry

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“…There are several reports describing that ODC inhibitor induces cell cycle arrest (24,25). In these papers, DFMO induced G 1 arrest in HuTu-80, HT-29, MCF-7, A-427, and CHO cells.…”

Section: Discussionmentioning

confidence: 96%

p53 Independent G1 Arrest Induced by -α-Difluoromethylornithine

Nemoto

Kamei

Seyama

et al. 2001

Biochemical and Biophysical Research Communications

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“…Fredlund and Oredsson (28) showed that polyamine-depleted Chinese hamster ovary cells entered the S phase of cell cycle at normal rate, but the progression through the S phase was delayed. Depletion of putrescine and spermidine pools was accompanied by impaired DNA replication, whereas no changes occurred in the rate of RNA and protein synthesis.…”

Section: Tablementioning

confidence: 99%

Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis

Hyvönen

Keinänen

Cerrada-Gimenez

et al. 2007

Journal of Biological Chemistry

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We have earlier shown that ␣-methylated spermidine and spermine analogues rescue cells from polyamine depletion-induced growth inhibition and maintain pancreatic integrity under severe polyamine deprivation. However, because ␣-methylspermidine can serve as a precursor of hypusine, an integral part of functional eukaryotic translation initiation factor 5A required for cell proliferation, and because ␣,-bismethylspermine can be converted to methylspermidine, it is not entirely clear whether the restoration of cell growth is actually attributable to hypusine formed from these polyamine analogues. Here, we have used optically active isomers of methylated spermidine and spermine and show that polyamine depletion-induced acute cytostasis in cultured cells could be reversed by all the isomers of the methylpolyamines irrespective of whether they served or not as precursors of hypusine. In transgenic rats with activated polyamine catabolism, all the isomers similarly restored liver regeneration and reduced plasma ␣-amylase activity associated with induced pancreatitis. Under the above experimental conditions, the (S,S)-but not the (R,R)-isomer of bismethylspermine was converted to methylspermidine apparently through the action of spermine oxidase strongly preferring the (S,S)-isomer. Of the analogues, however, only (S)-methylspermidine sustained cell growth during prolonged (more than 1 week) inhibition of polyamine biosynthesis. It was also the only isomer efficiently converted to hypusine, indicating that deoxyhypusine synthase likewise possesses hidden stereospecificity. Taken together, the results show that growth inhibition in response to polyamine depletion involves two phases, an acute and a late hypusine-dependent phase.A large number of studies have indicated that a continuous supply of the polyamines (spermidine and spermine) is required for animal cell proliferation to occur as polyamine depletion resulted either from a specific inhibition of their biosynthesis (1) or from an activation of their catabolism (2) invariably leads to growth inhibition. The molecular mechanisms involved in the requirement of polyamines for animal cell growth are largely unknown besides the fact that spermidine, but not spermine, serves as the sole biosynthetic precursor for hypusine, an unusual amino acid that is an integral component of eukaryotic translation initiation factor 5A (eIF5A) 4 (3). Because functional (hypusinated) eIF5A is required for animal cell growth (4, 5), it is often difficult to judge whether spermidine depletion-induced growth inhibition is secondary to hypusine deprivation. The finding that cytostasis resulting from an inhibition of S-adenosylmethionine decarboxylase in cultured cells is reversed by ␣-methylspermidine (MeSpd) but not by ␣,-bismethylspermine (Me 2 Spm) indicates that growth inhibition was attributable to hypusine depletion as MeSpd, but not Me 2 Spm, can serve as the biosynthetic precursor for hypusine formation (6). On the other hand, MeSpd and both singly and doubly methylated spermine deri...

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Impairment of DNA Replication within One Cell Cycle after Seeding of Cells in the Presence of a Polyamine‐Biosynthesis Inhibitor

Cited by 23 publications

References 28 publications

Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle

Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle

p53 Independent G1 Arrest Induced by -α-Difluoromethylornithine

Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis

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Impairment of DNA Replication within One Cell Cycle after Seeding of Cells in the Presence of a Polyamine‐Biosynthesis Inhibitor

Cited by 23 publications

References 28 publications

Treatment of cells with the polyamine analog N1,N11‐diethylnorspermine retards S phase progression within one cell cycle

Treatment of cells with the polyamine analog N1,N11‐diethylnorspermine retards S phase progression within one cell cycle

p53 Independent G1 Arrest Induced by -α-Difluoromethylornithine

Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis

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Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle

Treatment of cells with the polyamine analog N¹,N¹¹‐diethylnorspermine retards S phase progression within one cell cycle