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

Abstract

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...

Arginine transport in human erythroid cells: discrimination of CAT1 and 4F2hc/y+LAT2 roles

“…Since changes in arginine-derived metabolites, such as nitric oxide and polyamines, are known to influence erythroid differentiation [7,8,[16][17][18]21], modifications of intracellular arginine availability may alter the metabolism of the cationic amino acid and hence have physiological relevance. In this context, if CAT1-mediated arginine influx is needed for erythroid differentiation [23,29], the y + LAT2-mediated efflux of the amino acid may behave as a brake, avoiding excessive increase in the intracellular arginine concentration and inappropriate activation of metabolic pathways during the differentiation process.…”

“…Moreover, the differentiation of erythroid precursors requires polyamines [21] and arginase; this enzyme catalyzes the first step in polyamine biosynthesis and is induced during the differentiation of K562 cells promoted by sodium phenylbutyrate [18]. Hence, it is not surprising that the availability of extracellular arginine, the precursor of both nitric oxide and polyamines, influences the expression of globin genes [16].…”

Effects of a putrescine analog on Giardia lamblia

“…Polyamines were also shown to regulate cell differentiation in several cell types (Fernandez-Pinilla and Pestana 1987;Gavin et al 2004;Pietila et al 2005;Maeda et al 2006). The encystment-specific vesicles (ESV) and clefts Fig.…”

Decreased Proliferation and Erythroid Differentiation of K562 Cells by siRNA-induced Depression of OCTN1 (SLC22A4) Transporter Gene

“…We previously reported that OCTN1 was strongly expressed in glycophorin A-positive erythroid cells and was associated with erythroid-lineage cells at the transition stage from immature erythroid cells to peripheral mature erythrocytes (7). In addition, the small molecules that are transported by transporters such as, L -arginine, polyamine, and thiamine are associated with cell differentiation (15,25,26). Accordingly, it is considered that OCTN1 physiologically transports small molecule(s) that are essential for normal cell growth and differentiation to erythrocytes.…”