Spermine induces haemoglobin synthesis in murine erythroleukaemia cells

Delcros, Jean‐Guy; Schwartz, Benjamin D.; Clément, Sophie; Basu, Hirak S.; Marton, L. J.; Feuerstein, Burt G.

doi:10.1042/bj3090781

Cited by 5 publications

(7 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…31,32 On the other hand, polyamines, which are produced from L-ornithine through L-arginine, induce hemoglobin synthesis in murine erythroleukemia cells. 33 In contrast, there is a report that amino acid starvation induces differentiation through an amino acid response element like C/EBP homologous protein, 34 but this seems to be a different phenomenon not involving a transporter.…”

Section: Discussionmentioning

confidence: 96%

l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

Shima

Maeda

Aizawa

et al. 2006

Blood

View full text Add to dashboard Cite

In the present study, we examined the role in hematopoiesis of cationic amino acid transporter 1 (CAT1) , IntroductionCytokines such as interleukin-3 (IL-3) and erythropoietin play an important role in the differentiation of hematopoietic stem cells. 1,2 However, the roles of small molecules such as vitamins, nucleic acids, and amino acids in cell differentiation have not been elucidated well, though it is likely that specific transporters are involved in importing such small hydrophilic molecules into the cells. The ABC transporter Bcrp1 (abcg2) is expressed mainly in hematopoietic stem cells, 3 and more recently, efflux transporter activities in murine hematopoietic stem cells (HSCs) were found to vary according to developmental and activation status. 4 Thiamine transporter Thtr-1 (slc19a2) gene knockout mice showed abnormalities of erythroid, myeloid, and megakaryocyte lineages in bone marrow when fed a thiamine-free diet. 5 The importance of CAT1 (cationic amino acid transporter)-mediated transport was recently underscored by the production of cat1 gene knockout mice, which exhibit anemia. 6 These reports indicate that substrates of transporters expressed on hematopoietic stem cells are physiologically essential in differentiation or proliferation of the cells, or both, and the expression levels and activities of these transporters are likely to be regulated stage and lineage specifically.Cationic amino acid transporter (CAT, slc7a), known as system y ϩ , transports cationic amino acids such as L-lysine, L-histidine, L-ornithine, and L-arginine. 7-9 System y ϩ is a facilitative process that is Na ϩ -independent and pH insensitive. CAT1 (slc7a1), whose mouse ortholog was first identified as a virus receptor, 10,11 is expressed ubiquitously, including fetal liver and bone marrow, though not adult liver. 12 It is known that fetal and embryonic liver plays a significant role in hematopoiesis. 13 Furthermore, CAT1 mRNA is induced in regenerating liver in a short-lived manner and has multiple sites for regulation of gene expression, indicating that system y ϩ is tightly regulated and essential for liver cells to enter mitosis. 14,15 These findings suggest that CAT1 could be involved in hematopoietic activity.One of the substrates of CAT1, L-arginine, is a precursor of nitric oxide (NO) and polyamines. NO can induce apoptosis in megakaryocytes and platelet formation. 16,17 L-ornithine is produced by arginase and further metabolized to polyamines, which regulate the cell cycle. 18 Recently, low concentrations of L-glutamine were reported to induce functional differentiation of U937 myelomonocytic cells. 19 These facts suggest that low-molecular-weight molecules such as amino acids may be involved in hematopoiesis, as well as large-molecular cytokines such as IL-3 and erythropoietin. In the present study, we investigated the effects of hCAT1 expression level and L-arginine on differentiation and proliferation of human cord blood cells and a cloned human erythroid model, K562 cells. Materials and methods Tissue cultur...

show abstract

Section: Discussionmentioning

confidence: 96%

l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

Shima

Maeda

Aizawa

et al. 2006

Blood

View full text Add to dashboard Cite

show abstract

“…Among polyamines, spermine was reported to induce hemoglobin synthesis in murine erythroleukemic cell line MEL cells. 18) Since K562 cells were differentiated by butyrate, in the present study the effect of polyamines on the butyrate-dependent differentiation of K562 cells was examined.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, it was shown that polyamine itself could not induce the growth or differentiation of K562 cells to erythrocytes and the differentiation mechanism of human leukemia K562 cells was apparently different from that observed in mouse erythroleukemic MEL cells. 18) Next, we investigated the effect of polyamines in the presence of sodium butyrate, whether polyamines could complement the role of L-arginine. However, polyamines did not induce any differentiation or proliferation of K562 cells in the absence of L-arginine and rather reduced the cell growth depending on the examined concentration (Figs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Polyamines Derived from Arginine in Differentiation and Proliferation of Human Blood Cells

Maeda

Wakasawa

Shima

et al. 2006

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The murine cationic amino acid transporter 1 (mCAT1) protein mediates membrane transports of L-arginine, L-lysine, L-histidine, and L-ornithine. The importance of mCAT1-mediated transport was underscored by the phenotype of mCAT1 gene-knockout mice, which exhibit anemia. 1) In addition, we reported that L-arginine that is a substrate of CAT1 is essential for the differentiation to erythrocyte by in vitro cell culture study.2) It has been also observed that L-arginine deficiency affects maturation of early B cells in the bone marrow, but not development of the T cells in the thymus. 3)However, the detailed biological role of the L-arginine in proliferation and differentiation of blood cells and K562 cells that are human leukemia cell line is not clear. L-Arginine is the precursor of polyamines, nitric oxide (NO), and agmatine that are associated with cell proliferation and differentiation.4) While NO can induce an apoptosis of megakaryocytes and a formation of platelet, 5,6) it was reported that NO inhibited differentiation of K562 cells. 7) L-Ornithine is produced by arginase and further metabolized into polyamines such as putrescine, spermidine and spermine, which regulate the cell cycle.8) Moreover, there is some evidence that agmatine acts as an antiproliferative molecule through induction of the protein antizyme.9) Antizyme inhibits ornithine decarboxylase (ODC), hence polyamine biosynthesis. At the same time, antizyme suppresses polyamine uptake. Based on these reports, it was considered that polyamines might be metabolic products of L-arginine that can facilitate differentiation of hematopoietic precursors to erythrocytes.Polyamines (putrescine, spermidine and spermine) play a crucial role in regulating gene expression, signal transduction, ion channel function, DNA and protein synthesis, as well as cell proliferation and differentiation.10) The intracellular polyamine concentration in human erythrocytes is reported to be relatively high; putrescine 0.6 mM (males), and 0.9 mM (females); spermidine 18 and 24 mM; spermine 19 and 15 mM. 11) Polyamines are also scavengers of reactive oxygen species, thereby protecting DNA, protein, and lipids from oxidative damage.12) Available evidence shows that polyamines are key regulators of angiogenesis, early mammalian embryogenesis, placental trophoblast growth, and embryonic development.13) The cellular polyamines are thought to be supplied through de novo synthesis from L-arginine and transport, while the mammalian polyamine transporter gene has not been identified, 14,15) unlike bacterial and/or fungal polyamine transporter. 10,16) De novo polyamine synthesis is governed in part by the activity of ornithine decarboxylase (ODC), which catalyzes the conversion of the amino acid, L-ornithine to the diamine and putrescine. When the ODC activity was inhibited by alpha-difluoromethylornithine (DFMO) in K562 cells, proliferation of K562 cells was inhibited through abolishment of intracellular polyamines.17) It was also reported that spermine induced hemoglobin production i...

show abstract

“…Polyamines are biological polycations that play a major role in cell growth and differentiation [1,2]. In murine erythroleukaemia (MEL) cells, spermine and synthetic polyamine analogues induce haemoglobin synthesis [3,4]. In a previous study, we related the ability of polyamine analogues to induce haemoglobin synthesis in this cell line to the number of cationic charges they possess [4].…”

Section: Introductionmentioning

confidence: 99%

Spermine uptake is necessary to induce haemoglobin synthesis in murine erythroleukaemia cells

Clément

Delcros

Feuerstein

1995

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

To determine whether intracellular uptake of spermine is necessary to induce haemoglobin synthesis in murine erythroleukaemia (MEL) DS 19 cells, we used single-step selection for resistance to N1,N12-bis(ethyl)spermine (BESM), a cytotoxic spermine analogue, to isolate clones deficient in polyamine transport. The cells were approximately 500-fold more resistant to BESM than parental cells and were unable to accumulate BESM, putrescine, spermidine or spermine. Addition of spermine to the polyamine-transport-deficient cells failed to induce haemoglobin synthesis. Hexamethylene-1,6-bisacetamide, a well-known differentiating agent, induced haemoglobin synthesis in both parental and resistant cells. Polyamine-transport-deficient cells transfected with DNA purified from the parental cell line were further selected for their ability to grow in the presence of alpha-difluoromethylornithine and putrescine. The transfectants had an active transport system for polyamines, and spermine added to their culture medium accumulated inside the cells and induced haemoglobin production. These findings indicate that intracellular spermine uptake is required to induce haemoglobin production in MEL cells.

show abstract

Spermine induces haemoglobin synthesis in murine erythroleukaemia cells

Cited by 5 publications

References 35 publications

l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

Role of Polyamines Derived from Arginine in Differentiation and Proliferation of Human Blood Cells

Spermine uptake is necessary to induce haemoglobin synthesis in murine erythroleukaemia cells

Contact Info

Product

Resources

About