Review
Modulation of cellular function by polyamines

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Abstract

Polyamines (putrescine, spermidine and spermine) are essential for normal cell growth. The polyamine levels in cells are regulated by biosynthesis, degradation, and transport. Polyamines can modulate the functions of DNA, nucleotide triphosphates, proteins, and especially RNA because most polyamines exist in a polyamine–RNA complex in cells. Thus, the major focus on this review is on the role of polyamines in protein synthesis. In addition, effects of polyamines on B to Z conversion of DNA, transcription, phosphorylation of proteins, cell cycle progression, apoptosis and ion channels, especially NMDA receptors, are outlined. The function of eIF5A is also briefly discussed. Finally, a correlation between acrolein, produced from polyamines by polyamine oxidases, and chronic renal failure or brain stroke is summarized. Increased levels of polyamine oxidases and acrolein are good markers of chronic renal failure and brain stroke.

Introduction

Polyamines [putrescine, NH2(CH2)4NH2; spermidine, NH2(CH2)3NH(CH2)4NH2; and spermine, NH2(CH2)3NH(CH2)4NH(CH2)3NH2] are essential for cell growth from bacteria to mammalian cells (Cohen, 1998, Igarashi and Kashiwagi, 2000, Tabor and Tabor, 1984). Because polyamines are fully protonated under physiological conditions, they can interact with nucleic acids, especially with RNA, ATP, specific kinds of proteins, and phospholipids (Miyamoto et al., 1993, Watanabe et al., 1991). In this review, the physiological functions of polyamines are discussed mainly with a focus on their interactions with RNA and subsequent effects on protein synthesis. Interactions of polyamines with DNA, ATP and specific kinds of proteins are also discussed. Polyamines have characteristics which are different from those of K+ and Mg2+ for their interaction with RNA and other acidic substances. In this context, it is also of interest to know why, among polyamines, putrescine and spermidine predominate in prokaryotic cells, which grow rapidly, whereas spermidine and spermine predominate in eukaryotic cells, which proliferate relatively slowly. We propose a hypothesis about this aspect of polyamine biology.

Section snippets

Regulation of polyamine contents in cells

The polyamine content of cells is elaborately regulated by biosynthesis, degradation, uptake and excretion (Igarashi and Kashiwagi, 1999, Pegg, 1988, Wallace et al., 2003). In both prokaryotes and eukaryotes, polyamine levels are increased during cellular responses to proliferative stimuli (Igarashi et al., 1975, Kakinuma et al., 1988, Marton and Pegg, 1995). Fig. 1 shows the metabolism of the polyamines in mammalian cells. Putrescine is synthesized from ornithine by ornithine decarboxylase

Polyamine distribution in mammalian cells and Escherichia coli

Cellular polyamine content increases in parallel with the cell proliferation rate, and polyamines interact with acidic substances like nucleic acids. To understand the physiological functions of polyamines, it is important to determine the distribution of polyamines among acidic substances in cells. We estimated the distribution of polyamines in bovine lymphocytes, rat liver and E. coli from the binding constants of polyamines to macromolecules (DNA, RNA and phospholipids) and nucleotide

Modulation of RNA-related functions by polyamines

The effects of polyamines on protein synthesis have been studied primarily in the context of their effects on RNA-related functions. We found that polyamines have not only a sparing effect on the Mg2+ requirement for protein synthesis but also a stimulating effect, which cannot be fulfilled by any amount of Mg2+ (Atkins et al., 1975, Igarashi et al., 1974, Kashiwagi et al., 1990). These results suggest that the structural change of RNA caused by polyamine binding is different from that caused

Modulation of DNA- and ATP-related functions by polyamines

Polyamines weakly interact with DNA and ATP (Table 1). In bovine lymphocytes, spermidine and spermine are estimated to bind to 0.46 and 0.79 mol/100 mol phosphates of DNA, respectively. Similarly, in rat liver, spermidine and spermine are estimated to bind to 0.19 and 0.19 mol/100 mol phosphates of DNA, respectively. If polyamines recognize specific nucleotide sequences preferentially, polyamines may have some effects at the DNA level. In this regard, it was shown that low concentration of

Modulation of cell cycle progression and apoptosis by polyamines

It is known that polyamine deficiency delays cell cycle progression, with most cells arrested at the G1/S boundary—i.e., the rate of DNA synthesis is decreased by polyamine deficiency. Under these conditions, the level of p27Kip1 and p21Cip1/WAF1, inhibitors of cyclin-dependent protein kinases CDK2 and CDK4, was increased (Choi et al., 2000, Ray et al., 1999). However, the mechanism of the increase in p27Kip1 and p21Cip1/WAF1 is still unknown. There are reports that inhibition of DNA synthesis

Modulation of the functions of ion channels by polyamines

As mentioned above, polyamines did not bind to cytoplasmic proteins significantly. However, specific interactions of polyamines, in particular spermine, with some types of ion channels have been reported (Williams, 1997). Intracellular spermine is responsible for intrinsic gating and rectification of strong inward rectifier K+ channels by direct plugging the ion channel pore. These K+ channels control the resting membrane potential in both excitable and non-excitable cells (Ficker et al., 1994,

Function of eIF5A

Eukaryotic initiation factor 5A (eIF5A) contains a unique spermidine-dependent hypusine modification on a specific lysine residue (Cooper et al., 1983), and the hypusine modification is essential for cell growth (Schnier et al., 1991). We have shown that eIF5A and polyamines are independently involved in cell growth (Nishimura et al., 2005). Two broad functions of eIF5A have been proposed. One is concerned with turnover of mRNA, acting downstream of decapping—the decapped non-functional mRNA

Clinical application of acrolein produced from polyamines

It is well known that the addition of spermidine or spermine to culture medium containing ruminant serum inhibits cell growth (Higgins et al., 1969). This effect is caused by the oxidation of polyamines by serum amine oxidase (Bachrach, 1970). Serum amine oxidase catalyzes the oxidative deamination of spermidine and spermine to produce hydrogen peroxide (H2O2) and aminoaldehyde, which spontaneously forms acrolein (CH2double bondCHCHO) (Tabor et al., 1964). Acrolein was found to be the major inhibitory

Future perspectives

Polyamines are essential for cell growth and differentiation. Physiological functions of polyamines are gradually being clarified at the molecular level. Our results strongly suggest that polyamine effect on cell growth mainly occurs at the level of translation. Clinical use of acrolein, a product of polyamine oxidation, is also promising. However, an important problem still remains to be resolved: i.e., rapidly growing prokaryotes mainly contain putrescine (diamine) and spermidine (triamine),

Acknowledgments

We are grateful to Dr. K. Williams for critical reading of the manuscript prior to submission. This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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