p53 Independent G1 Arrest Induced by -α-Difluoromethylornithine

Nemoto, Takahiro; Kamei, Shigeru; Seyama, Yousuke; Kubota, Shunichiro

doi:10.1006/bbrc.2000.4227

Cited by 15 publications

(13 citation statements)

References 23 publications

(26 reference statements)

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“…In agreement with previous reports in other experimental systems (22,23), DFMO caused an early and striking increase in p21 expression. Furthermore, we show here that the drug induced p21 association with cdk-2.…”

Section: Discussionsupporting

confidence: 93%

“…to induce a G 1 -S arrest in both normal and transformed cells (21)(22)(23). In this report, we show that the polyamine biosynthetic inhibitor DFMO caused a G 1 -S arrest and a G 2 -M block also in MDA-MB-435 breast cancer cells.…”

Section: Discussionmentioning

confidence: 50%

“…In other experimental systems, DFMO treatment has been shown to induce a parallel increase in p53 and p21 expressions (23). However, when the cause-effect relationship of these effects was tested, under conditions of polyamine depletion, p53 stimulation was not found to mediate the increase in p21 (22,29).…”

Section: Discussionmentioning

confidence: 92%

“…Nemoto et al (22) reported that induction of p21 expression by DFMO in MKN45 human gastric cancer cells was mediated by increased phosphorylation and binding of STAT1 to the promoter region of p21 followed by activation of transcription. Of interest, we have observed that DFMO treatment of MDA-MB-435 cells caused a marked increase in tyrosine phosphorylation of STAT1 (31), thus raising the possibility that this may be at least one of the mechanisms by which DFMO increases p21 expression in our system.…”

Section: Discussionmentioning

confidence: 99%

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Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells

Washington

Verderame

et al. 2005

Cancer Research

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Inhibition of polyamine biosynthesis with A-difluoromethylornithine (DFMO) has been shown to inhibit proliferation of breast cancer cells although its mechanism of action has not been fully elucidated. To address this issue, we tested the effects of DFMO on cell cycle variables of MDA-MB-435 human breast cancer cells in culture. We also focused on the possible mediatory role of the mitogen-activated protein kinase (MAPK) pathway on the cell cycle effects of DFMO because this compound has been shown to activate MAPK signaling. We found that DFMO caused a p53-independent increase in p21 and its association with cyclin-dependent kinase (cdk)-2 and decreased cdk-2 protein as well as its phosphorylation on Thr160. In addition, DFMO markedly suppressed the expression of the full-length and low molecular weight forms of cyclin E. These effects of DFMO were reversible with exogenous putrescine, thus indicating that they are specifically mediated through polyamine depletion. Cdk-2 activity was drastically reduced in DFMO-treated breast cancer cells which exhibited a reduction in retinoblastoma (Rb) phosphorylation and protein. As a predictable consequence of these effects, DFMO caused a G 1 -S block. In addition, DFMO inhibited G 2 -M transition, most likely as a result of its induction of p21 expression. Inhibition of the MAPK pathway with PD98059 or U0126 blocked the DFMO-induced induction of p21 and the reduction of cdk-2 protein. PD98059 reversed the G 2 -M block induced by DFMO (probably as a result of suppression of p21) but not the G 1 -S arrest. MDA-MB-435 cells treated with PD98059 or U0126 in the presence and absence of DFMO exhibited a marked increase in the expression of p27 and its association with cdk-2, a decrease in phosphorylation of cdk-2 on Thr160, and a decrease in cyclin E expression. As predicted, PD98059 treatment reduced cdk-2 activity and Rb phosphorylation while reversing the decrease in Rb protein induced by DFMO. Neither DFMO nor PD98059, either alone or in combination, reduced cdk-4 activity despite a marked induction in p15 expression caused by DFMO. Our results indicate that activation of the MAPK pathway accounts for some of the effects of DFMO on cell cycle events of breast cancer cells. Inhibition of the MAPK pathway, however, does not reverse the cell cycle arrest induced by DFMO because of activation of alternative mechanisms leading to suppression of cdk-2 activity. (Cancer Res 2005; 65(23): 11026-33)

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells

Washington

Verderame

et al. 2005

Cancer Research

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“…Global expression profiling after treatment with cytostatic drugs has been performed in cancer (62,63) but not in multistage organisms such as P. falciparum. Although the cytostatic effects of DFMO and MDL73811 are well established, the exact mechanism by which the induced polyamine depletion results in growth inhibition is not clear (64). In this investigation, the transcriptional arrest preceding and resulting in cytostatic growth arrest due to polyamine depletion was demonstrated for the first time to our knowledge in any organism.…”

Section: Discussionmentioning

confidence: 71%

Co-inhibition of Plasmodium falciparum S-Adenosylmethionine Decarboxylase/Ornithine Decarboxylase Reveals Perturbation-specific Compensatory Mechanisms by Transcriptome, Proteome, and Metabolome Analyses

Brummelen

Olszewski

Wilinski

et al. 2009

Journal of Biological Chemistry

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Polyamines are ubiquitous components of all living cells, and their depletion usually causes cytostasis, a strategy employed for treatment of West African trypanosomiasis. To evaluate polyamine depletion as an anti-malarial strategy, cytostasis caused by the co-inhibition of S-adenosylmethionine decarboxylase/ ornithine decarboxylase in Plasmodium falciparum was studied with a comprehensive transcriptome, proteome, and metabolome investigation. Highly synchronized cultures were sampled just before and during cytostasis, and a novel zero time point definition was used to enable interpretation of results in lieu of the developmentally regulated control of gene expression in P. falciparum. Transcriptome analysis revealed the occurrence of a generalized transcriptional arrest just prior to the growth arrest due to polyamine depletion. However, the abundance of 538 transcripts was differentially affected and included three perturbation-specific compensatory transcriptional responses as follows: the increased abundance of the transcripts for lysine decarboxylase and ornithine aminotransferase and the decreased abundance of that for S-adenosylmethionine synthetase. Moreover, the latter two compensatory mechanisms were confirmed on both protein and metabolite levels confirming their biological relevance. In contrast with previous reports, the results provide evidence that P. falciparum responds to alleviate the detrimental effects of polyamine depletion via regulation of its transcriptome and subsequently the proteome and metabolome.Polyamines such as putrescine, spermidine, and spermine are small organic compounds containing two or more amino groups. At physiological pH, these polycations interact electrostatically with numerous anionic macromolecules, thereby stabilizing DNA, RNA, nucleoside triphosphates (e.g. ATP), phospholipids, and proteins (1, 2). These interactions with polyamines can alter DNA conformation, regulate replication and transcription, strengthen membranes, regulate ion channels, and protect DNA and phospholipids from oxidative stress (1-5). Yet polyamines are also implicated in apoptosis (5). Polyamine depletion generally causes cytostasis or growth arrest, which implies that these molecules are involved in cell cycle progression and regulation, and it is speculated that polyamines regulate cyclin degradation (1, 6, 7). Therefore, polyamines are essential for cellular growth, differentiation, and macromolecular synthesis and are ubiquitous components of all living cells, except two orders of Archaea (1). Polyamine metabolism is particularly important in rapidly proliferating cells and has been exploited in the treatment of cancer (1) and parasitic diseases (8). Polyamine metabolism of the malaria parasite Plasmodium falciparum is also a potential target for therapeutic intervention (9, 10).Polyamine and methionine metabolism are closely connected. This is particularly evident in Plasmodium where the two rate-limiting enzymes of polyamine biosynthesis, ornithine decarboxylase (ODC) 2 and S-adenosylme...

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Ornithine decarboxylase overexpression enhances ERK and p38 phosphorylation and matrix metalloproteinase‐2 expression

Nemoto

Kubota

2007

Cell Biology International

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In the present study, we investigated the relationship between ornithine decarboxylase, MAP kinase, and MMP-2 expression in vitro. Overexpression of ornithine decarboxylase cDNA induced MMP-2 expression both at mRNA and protein levels. Promoter analysis and gel shift assay showed that p53 and Ets-1 were involved in MMP-2 expression in ornithine decarboxylase overexpressing transfectants. Erk and p38 MAP kinase were significantly activated. Using specific inhibitors of MEK and p38, we clarified that MMP-2 expression was induced via both Erk and p38 MAP kinase signaling pathways. This is the first report showing the existence of a causal relationship between ornithine decarboxylase expression, Erk and p38 MAP kinase activation, and MMP-2 expression.

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p53 Independent G1 Arrest Induced by -α-Difluoromethylornithine

Cited by 15 publications

References 23 publications

Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells

Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells

Co-inhibition of Plasmodium falciparum S-Adenosylmethionine Decarboxylase/Ornithine Decarboxylase Reveals Perturbation-specific Compensatory Mechanisms by Transcriptome, Proteome, and Metabolome Analyses

Ornithine decarboxylase overexpression enhances ERK and p38 phosphorylation and matrix metalloproteinase‐2 expression

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