Mimosine Blocks Cell Cycle Progression by Chelating Iron in Asynchronous Human Breast Cancer Cells

Kulp, Kristen S.; Vulliet, Philip R

doi:10.1006/taap.1996.0176

Cited by 60 publications

(43 citation statements)

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“…Both the increase in Drg-1 expression and inhibition of eIF5A modification induced by mimosine treatment occurred prior to the G 1 /S cell cycle arrest. Mimosine has been reported to act as an iron chelator and as an inhibitor of DOHH (26,27,35,36), the enzyme responsible for the second step in the biosynthesis of the unique amino acid hypusine in eIF5A. Our results further suggest that the mimosine-induced early increase in Drg-1 expression is not due to a decrease in mature eIF5A formation or to the inhibition of DOHH.…”

Section: Comparison Of the Effects Of Mimosine On Drg-1 Expression Wisupporting

confidence: 55%

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Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

Dong

Arnold

Yang

et al. 2005

Molecular & Cellular Proteomics

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L-Mimosine, a plant amino acid, can reversibly block mammalian cells at late G 1 phase and has been found to affect translation of mRNAs of the cyclin-dependent kinase inhibitor p27, eIF3a (eIF3 p170), and ribonucleotide reductase M2. The effect of mimosine on the expression of these genes may be essential for the G 1 phase arrest. To determine additional genes that may be early respondents to the mimosine treatment, we performed two-dimensional gel electrophoretic analysis of [35 S]methionine-labeled cell lysates followed by identification of the altered protein spots by LC-tandem mass spectrometry. In this study, the synthesis of two protein spots (MIP42 and MIP17) was found to be enhanced by mimosine, whereas the formation of another protein spot (MSP17) was severely blocked following mimosine treatment. These protein spots, MIP42, MIP17, and MSP17, were identified to be differentiation-related gene 1 (Drg-1; also called RTP, cap43, rit42, Ndrg-1, and PROXY-1), deoxyhypusine-containing eIF5A intermediate, and mature hypusine-containing eIF5A, respectively. The effect of mimosine on eIF5A maturation was due to inhibition of deoxyhypusine hydroxylase, the enzyme catalyzing the final step of hypusine biosynthesis in eIF5A. The mimosine-induced expression of Drg-1 was mainly attributable to increased transcription likely by the c-Jun/AP-1 transcription factor. Because induction of Drg-1 is an early event after mimosine treatment and is observed before a notable reduction in the steady-state level of mature eIF5A, eIF5A does not appear to be involved in the modulation of Drg-1 expression. Molecular & Cellular Proteomics 4:993-1001, 2005.

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Section: Comparison Of the Effects Of Mimosine On Drg-1 Expression Wisupporting

confidence: 55%

“…Previously it has been shown that mimosine functions as an iron chelator (10,35,36). Although chelating iron would increase the expression and activity of HIF-1 and c-Jun/AP-1 transcription factors (30), it also decreases the expression and activity of N-Myc and c-Myc (47,48).…”

Section: Comparison Of the Effects Of Mimosine On Drg-1 Expression Wimentioning

confidence: 99%

Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

Dong

Arnold

Yang

et al. 2005

Molecular & Cellular Proteomics

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“…Previously, we have characterized folate metabolism in both cultured human MCF-7 cells and SH-SY5Y neuroblastoma (16,22) and have used these cell lines to study the role of SHMT in folate metabolism. Whereas mimosine has been demonstrated to inhibit both human breast cancer (MDA-MB-453) (10) and Chinese hamster ovary cell proliferation (23), the effect of mimosine on MCF-7 and SH-SY5Y neuroblastoma cell proliferation has never been investigated. MCF-7 cells exposed to 350 M mimosine incorporate less than 5% of [methyl-3 H]thymidine into DNA relative to untreated MCF-7 cells after a 24 h exposure to mimosine (Fig.…”

Section: Mimosine Targets Tumor Cell Lines With Specificity-sev-mentioning

confidence: 99%

Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Oppenheim

Nasrallah

Mastri

et al. 2000

Journal of Biological Chemistry

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Iron deficiency and iron chelators are known to alter folate metabolism in mammals, but the underlying biochemical mechanisms have not been established. Although many studies have demonstrated that the iron chelators mimosine and deferoxamine inhibit DNA replication in mammalian cells, their mechanism of action remains controversial. The effects of mimosine on folate metabolism were investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings indicate that mimosine is a folate antagonist and that its effects are cell-specific. MCF-7 cells cultured in the presence of 350 M mimosine were growth-arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine altered the distribution of folate cofactor forms in MCF-7 cells, indicating that mimosine targets folate metabolism. However, mimosine does not influence folate metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT) expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines demonstrate that although the effect of mimosine on cell cycle is independent of its effects on cSHMT expression, it inhibits both processes through a common regulatory mechanism.There are several well characterized cellular responses that are triggered following decreases in the regulatory, non-ferritin-bound iron pool. Many of these responses are mediated through the iron regulatory protein, which can bind with specificity to certain mRNA species and regulate translation (1). The concentration of cellular regulatory iron is decreased by iron deficiency or by elevated expression of heavy chain ferritin, a protein that sequesters intracellular iron (2, 3). Sequestration of intracellular iron by chelators, including DFO, 1 has been commonly used to trigger physiological changes associated with iron deficiency. The influence of iron deficiencies, both induced and naturally occurring, on folate metabolism has been well documented in cell culture models, animal models, and humans. Iron deficiency can result in morphological alterations in granulocytes similar to folate deficiency (4), and iron deficiency has been demonstrated to impair folate utilization in some but not all tissues (5). In addition, maternal iron deficiency decreases secretion of folate into milk (6, 7) without decreasing maternal serum or red blood cell folate levels in rats. However, the biochemical mechanisms underlying the influence of iron deficiency on folate metabolism have not been established (6).Mimosine, a plant amino acid and tyrosine analog ( Fig. 1), is a toxin that chelates iron and inhibits mammalian DNA replication. Mimosine is known to block DNA replication...

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“…Mimosine has been proposed to arrest DNA synthesis at the replication fork by repressing deoxyribonucleotide synthesis (9 -12). Mimosine and deferoxamine inhibit the activity of the iron-dependent enzyme ribonucleotide reductase in vitro by chelating iron (9,11,12) and deplete cellular deoxyribonucleotide pools in some but not all studies (2,12). Furthermore, mimosine and deferoxamine have been shown to inhibit the transcription of the cytoplasmic serine hydroxymethyltransferase gene (SHMT1) 1 in MCF-7 cells but not in mimosine-resistant SH-SY5Y neuroblastoma (2).…”

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confidence: 99%

“…Mimosine also affects gene expression at the level of transcription and translation. Mimosine increases the expression of p21 WAF-1 (5,15) and p27 kip1 (16) while decreasing the transcription of the SHMT1 (2), Mcp-1, and Mip-2 (17) genes and depleting cyclin D levels (11). Mimosine also inhibits the activity of several enzymes in vitro including tyrosinase, dopamine ␤-hydroxylase, deoxyhypusyl hydroxylase, and H1 kinase (3).…”

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confidence: 99%

Mimosine Attenuates Serine Hydroxymethyltransferase Transcription by Chelating Zinc

Perry

Sastry

Nasrallah

et al. 2005

Journal of Biological Chemistry

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L-Mimosine is a naturally occurring plant amino acid and iron chelator that arrests the cell cycle in the late G 1 phase, although its mechanism of action is not known. Some studies indicate that mimosine prevents the initiation of DNA replication, whereas other studies indicate that mimosine disrupts elongation of the replication fork by impairing deoxyribonucleotide synthesis by inhibiting the activity of the iron-dependent enzyme ribonucleotide reductase and the transcription of the cytoplasmic serine hydroxymethyltransferase gene (SHMT1). In this study, the mechanism for mimosineinduced inhibition of SHMT1 transcription was elucidated. A mimosine-responsive transcriptional element was localized within the first 50 base pairs of the human SHMT1 promoter by deletion analyses and gel mobility shift assays. The 50-base-pair sequence contains a consensus zinc-sensing metal regulatory element (MRE) at position ؊44 to ؊38, and mutation of the MRE attenuated mimosine-induced transcription repression. Mimosine treatment eliminated MRE-and Sp1-binding activity in nuclear extracts from MCF-7 cells but not in nuclear extracts from a mimosine-resistant cell line, MCF-7/2a. MCF-7 cells cultured in zinc-depleted medium for more than 16 days were viable and lacked cytoplasmic serine hydroxymethyltransferase protein, confirming that mimosine inhibits SHMT1 transcription by chelating zinc. The disruption of DNA-protein interactions by zinc chelation provides a general mechanism for the inhibitory effects of mimosine on nuclear processes, including replication and transcription. Furthermore, this study establishes that SHMT1 is a zinc-inducible gene, which provides the first mechanism for the regulation of folate-mediated one-carbon metabolism by zinc.Mimosine is an amino acid found in plants of the Mimosa and Leucaena genera and a tyrosine analog (1). It is a cell-specific inhibitor of DNA replication in vivo; sensitive cell lines include human MCF-7 (2), HL60 (3) and Chinese hamster ovary (4), whereas human neuroblastoma (2), K562 (3), and Xenopus and mouse embryonic cells are resistant (5, 6). Mimosine is an effective iron chelator and a structural analog of deferiprone, a compound that is used clinically to lower systemic iron in patients who suffer from iron overload (7, 8) (Fig. 1).Mimosine arrests cell cycle progression in late G 1 and although it elicits a plethora of biological effects, its mechanism of action has not been established. Mimosine has been proposed to arrest DNA synthesis at the replication fork by repressing deoxyribonucleotide synthesis (9 -12). Mimosine and deferoxamine inhibit the activity of the iron-dependent enzyme ribonucleotide reductase in vitro by chelating iron (9, 11, 12) and deplete cellular deoxyribonucleotide pools in some but not all studies (2, 12). Furthermore, mimosine and deferoxamine have been shown to inhibit the transcription of the cytoplasmic serine hydroxymethyltransferase gene (SHMT1) 1 in MCF-7 cells but not in mimosine-resistant SH-SY5Y neuroblastoma (2). The cytoplasmic ser...

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Mimosine Blocks Cell Cycle Progression by Chelating Iron in Asynchronous Human Breast Cancer Cells

Cited by 60 publications

References 0 publications

Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

Mimosine Is a Cell-specific Antagonist of Folate Metabolism

Mimosine Attenuates Serine Hydroxymethyltransferase Transcription by Chelating Zinc

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