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PubMed2006

Polyamine Modulon in Escherichia coli: genes involved in the stimulation of cell growth by polyamines.

We have recently proposed an idea to explain how polyamines enhance cell growth in Escherichia coli. Since most polyamines exist as polyamine-RNA complexes, our idea is that polyamines stimulate several kinds of protein synthesis which are important for cell growth at the level of translation. We found that synthesis of oligopeptide binding protein (OppA), which is important for nutrient supply, adenylate cyclase (Cya), RNA polymerase sigma(38) subunit (RpoS), transcription factor of iron transport operon (FecI), and transcription factor of growth-related genes including rRNA and some kinds of tRNA synthesis (Fis) was enhanced by polyamines at the level of translation. We proposed that a group of genes whose expression is enhanced by polyamines at the level of translation be referred to as a "polyamine modulon." By DNA microarray, we found that 309 of 2,742 mRNA species were up-regulated by polyamines. Among the 309 up-regulated genes, transcriptional enhancement of at least 58 genes might be attributable to increased levels of the transcription factors Cya, RpoS, FecI, and Fis. This unifying molecular mechanism is proposed to underlie the physiological role of polyamines in controlling the growth of Escherichia coli.

Adenylyl Cyclases↗
PubMed2002

Dietary arginine slightly and variably affects tissue polyamine levels in male swiss albino mice.

Many key metabolic and physiologic functions involve arginine and arginine-derived metabolites. Requirements for arginine, a "conditionally essential" amino acid for most mammalian species, are met in variable proportions by dietary intake and endogenous synthesis, the latter being sufficient to fulfill arginine needs in adult humans and mice under nonpathologic conditions. However, dietary arginine restriction causes orotic aciduria and abnormal function of the urea cycle. Furthermore, the importance of dietary arginine in the maintenance of homeostasis of arginine-derived metabolites in the body has not yet been analyzed in detail. We therefore examined whether the deprivation or supplementation of dietary arginine affects tissue and circulating levels of arginine-derived polyamines. We pair-fed male Swiss albino mice (30 g) for 15 or 30 d synthetic diets containing 0, 1.12 or 2.24 g/100 g L-arginine. Tissue and blood levels of the main free polyamines, putrescine, spermidine and spermine, were measured by HPLC. In general, neither the deprivation nor the supplementation of arginine dramatically affected the levels of any of the polyamines analyzed. Variations were organ, time and polyamine specific, and most differences were in the levels of putrescine at 15 d and of spermidine at 30 d. Thus, in contrast to effects on urea cycle function, dietary arginine does not appear to be essential for the maintenance of the homeostasis of free polyamine levels in adult mice, emphasizing the importance of endogenous arginine synthesis in preserving the polyamine body pool.

Animals↗
PubMed2003

Polyamine flux in Xenopus oocytes through hemi-gap junctional channels.

Diverse polyamine transport systems have been described in different cells, but the molecular entities that mediate polyamine influx and efflux remain incompletely defined. We have previously demonstrated that spermidine efflux from oocytes is a simple electrodiffusive process, inhibitable by external Ca2+, consistent with permeation through a membrane cation channel. Hemi-gap junctional channels in Xenopus oocytes are formed from connexin 38 (Cx38), and produce a calcium-sensitive (Ic) current that is inhibited by external Ca2+. Spermidine efflux is also calcium sensitive, and removal of external calcium increases both Ic currents and spermidine efflux in Xenopus oocytes. Injection of Cx38 cRNA or Cx38 antisense oligonucleotides (to increase or decrease, respectively, Cx38 expression) also increases or decreases spermidine efflux in parallel. Spermidine efflux has a large voltage-dependent component, which is abolished with injection of Cx38 antisense oligonucleotides. In addition, spermidine uptake is significantly increased in Cx38 cRNA-injected oocytes in the absence of external calcium. The data indicate that hemi-gap junctional channels provide the Ca2+-inhibited pathway for electrodiffusive efflux of polyamines from oocytes, and it is likely that hemi-gap junctional channels provide Ca2+ and metabolism-sensitive polyamine permeation pathways in other cells.

Animals↗
PubMedDate not supplied

Apoptosis induction in human breast cancer MRK-nu-1 cells by a polyamine synthesis inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone)(MGBCP).

We have investigated the antiproliferative effects of a polyamine synthesis inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone) (MCBCP), on human breast cancer MRK-nu-1 cells. MGBCP inhibited tumor growth of MRK-nu-1 cells in a dose-dependent manner as the polyamine contents in the cells decreased. Moreover, morphological changes indicating blebbing and chromatin condensation were observed in the MGBCP-treated cells, and hypodiploid subpopulations containing apoptotic cells were clearly detected in the profile of flow cytometric analysis. The number of characteristic oligonucleosome-sized fragments also increased as the concentration of MGBCP increased. The apoptotic effects of MGBCP were partially prevented by the addition of exogenous spermine. The results presented here suggest that, in addition to reducing the growth rate, MGBCP can induce apoptotic cell death in MRK-nu-1 human breast cancer cells by the reduction of intracellular concentrations of polyamines.

Antineoplastic Agents↗
PubMed1995

Effect of neurotensin on pancreatic growth and pancreatic polyamine metabolism in rats.

The neuropeptide neurotensin is known to play a role in the regulation of exocrine pancreatic secretion, but actually there are conflicting results as to whether or not neurotensin exerts a trophic response on the pancreas and there are no data concerning its effect on pancreatic polyamine metabolism. In the present study, acute and long-term effects of various intraperitoneal dosages of neurotensin that resulted in mildly supraphysiological and even unphysiological high plasma concentrations of neurotensin were studied. Furthermore, neurotensin was simultaneously administered with cholecystokinin (1 microgram CCK-8/kg body wt ip every 8 h) for five days. The administration of neurotensin resulted in an acute significant decrease of pancreatic amylase and trypsinogen concentrations (p < 0.001), which indirectly confirms the potent effect of neurotensin on pancreatic exocrine secretion. In contrast to that, neither during the short-term study (100 micrograms neurotensin/kg body wt ip every 8 h for 2, 4, 6, 8, 16, and 24 h) nor during the long-term study (1 microgram, 100 micrograms, or 200 micrograms neurotensin/kg body wt ip three or eight times daily for 10 d) did neurotensin administration result in any increase of the various parameters of pancreatic growth and polyamine metabolism. Simultaneous administration of neurotensin and CCK failed to alter or further increase the known stimulatory effect of CCK on pancreatic polyamine metabolism and pancreatic growth after 5 d of treatment. These data indicate that neither alone nor in combination with cholecystokinin did various dosages of neurotensin exert any significant stimulation on pancreatic growth or the parameters of pancreatic polyamine metabolism.

Animals↗
PubMedDate not supplied

Behavioral and neurochemical sequelae in young rats of antenal hypoxia.

To test the hypothesis that perinatal hypoxia may have postnatal consequences via à vis learning memory, and neurochemical sequelae, we exposed pregnant Sprague-Dawley rats to 10.5% O2 for 4 h per day (0800-1200 h) or continuously from gestional day E15 to E20. On E20 we quantified ornithine decarboxylase activity and polyamine concentrations in fetal brain. We also conducted behavioral tests from postnatal day P3 to P110. Relatively mild antenatal hypoxia resulted in altered learning, memory, and delayed maturation of early developmental sensorimotor function. These behavioral changes disappeared at various postnatal ages, depending on the function. Perinatal hypoxia also altered the pharmacological response to dopaminergic drugs. In addition, antenatal hypoxia feminized a male nonreproductive sexual behavior, that of saccharin preference. Acute hypoxia also resulted in an increase in the enzyme ornithine decarboxylase and polyamines, which may affect brain development.

Animals↗
PubMed2001

Increase of the ornithine decarboxylase/polyamine system and transglutaminase upregulation in the spinal cord of aged rats.

We have investigated changes in ornithine decarboxylase (ODC) activity and in polyamine levels in the central nervous system of aged rats. We measured a significant increase of ODC catalytic activity in the spinal cord from 30 month-old rats (+105%) as compared to 4 month-old rats. No changes were noticed in the cerebellum, cortex and hippocampus from the same animals. A related putrescine increase was measured in the spinal cord of 30 month-old rats (+168%), together with a smaller increase of spermidine (+33%). A parallel increase (+78%) of the Ca2+-dependent transglutaminase activity was detected in the spinal cord of 30 month-old rats, while no changes were apparent in the cortex and cerebellum. Our observations indicate a possible role of the ODC/polyamine system during the normal process of ageing in rats and point to the spinal cord as the most sensitive area for this kind of modification. A possible role of protein polyamination by transglutaminase is discussed.

Aging↗
PubMed2001

Polyamines as cancer markers: applicable separation methods.

Spermine, spermidine, putrescine and cadaverine are aliphatic amines widely spread in the human body. Their concentrations together with their acetyl conjugates increase significantly in the biological fluids and the affected tissues of cancer patients. Their concentrations decrease with the improvement in the patient's condition on multiple therapy. Various chromatographic techniques are frequently used in monitoring concentrations of di- and polyamines in cancer. Among these techniques, thin-layer chromatography and liquid chromatography using pre- or postcolumn derivatization, separating on a reversed-phase or an ion-exchange column are the most commonly used. Besides, high-resolution capillary column gas chromatography (GC) is increasingly used over packed column GC, and in recent years, capillary zone electrophoresis has also gained some importance in polyamine determinations. The review examines the prospects and the limitations of polyamines as cancer markers using chromatographic and electrophoretic techniques.

Biogenic Polyamines↗
PubMed1997

Fasting and postprandial polyamine concentrations in the human digestive lumen.

Polyamines are essential to cellular proliferation and differentiation. The gastrointestinal tract could represent a major source of polyamines in the body; however, there is little information regarding the presence of polyamines in the human intestinal chyme, and the source of these intraluminal polyamines remains unclear. The aims of our study were to determine the concentrations and flow rates of polyamines in the human intestinal lumen and to estimate the contribution from food to these concentrations. Polyamine concentrations and flow rates were determined after 12 h of fasting in jejunal (n = 25) and ileal (n = 9) effluents collected by the slow-marker perfusion technique. Kinetic studies were performed after water ingestion (no polyamines) in the jejunum (n = 6) and ileum (n = 5) and in the jejunum after a yogurt test meal (polyamine content: 2.8 mumol putrescine, 2.1 mumol cadaverine, 2.1 mumol spermidine, and 1.9 mumol spermine; n = 9). There were significant polyamine concentrations in the lumen of the human gut during the fasting state, suggesting endogenous secretion. Higher polyamine concentrations were observed in the jejunum than in the ileum (P < 0.05), suggesting proximal absorption. Kinetic studies showed a 25% transitory increase in the jejunal putrescine flow rate after ingestion of the yogurt test meal, suggesting that dietary polyamines are fully absorbed.

Adult↗
PubMed1998

Polyamine uptake across the basolateral membrane of the enterocyte is mediated by a high-affinity carrier: a study using isolated basolateral membrane vesicles.

BACKGROUND/AIMS: Polyamine uptake from the circulation plays an important role in the maintenance of the intracellular polyamine content during extensive proliferation in intestinal mucosal cells. METHODS: Isolated basolateral membrane vesicles of the rabbit enterocyte were used to characterize polyamine transport across the basolateral side of the intestinal epithelium. Incorporation of spermidine and spermine into the basolateral membrane was rapid, although 30-60% of polyamines were initially bound to the basolateral membrane. In order to avoid the influence of binding on the actual uptake into the vesicles, polyamine incorporation was measured at 37 and 4 degrees C, and kinetic parameters were calculated from the difference in polyamine incorporation rates at these temperatures. RESULTS: Uptake kinetics was saturable, with Km values of 13.34 and 12.35 micromol/l and Vmax of 159 and 105 pmol/mg protein/ min for spermidine and spermine, respectively. It was also temperature dependent, with Q10 values (calculated between uptake velocities at 37 and 25 degrees C) of 2.56 for spermidine and 1.90 for spermine. At physiological pH, polyamine uptake was at its highest. Since at this pH polyamines are fully charged, charge might be essential for polyamines to be taken up across the basolateral membrane. Polyamine uptake was inhibited by di-, tri- and tetracations, and there was no evidence for sodium cotransport. Transport of putrescine was not inhibited by spermine and spermidine, although spermidine inhibited spermine uptake in a competitive manner, with Ki of 127 micromol/l. CONCLUSION: These results imply that a saturable high-affinity transport system for polyamine does exist at the basolateral side of the enterocyte. Such a transport system may be responsible for the active transport of polyamine into rapidly proliferating enterocytes.

Animals↗
PubMed1999

Polyamine depletion up-regulates c-Myc expression, yet induces G(1) arrest and terminal differentiation of F9 teratocarcinoma stem cells.

The ornithine decarboxylase (ODC) gene is a transcriptional target of c-Myc. Exponentially growing cells usually exhibit high c-Myc levels and high ODC levels, whereas stationary phase cells and terminally differentiated cells have low levels of both proteins. Therefore, we were surprised to find that when F9 teratocarcinoma stem cells were blocked in the G(1) phase of their cell cycle and induced to differentiate by irreversible inhibition of the ODC activity, the expression of c-Myc was up-regulated instead of being down-regulated. During the course of differentiation, the c-myc gene was constitutively expressed, and c-Myc protein accumulated. In transfection experiments, using ODC promoter-reporter gene fusion constructs, the accumulation of c-Myc protein, resulting from polyamine depletion, led to increased reporter gene expression. This finding is consistent with the view that depletion of polyamines relieves the suppression that they exert on c-myc mRNA translation, causing an accumulation of c-Myc protein, which in turn transactivates its target gene, the bona fide ODC gene. Thus, the accumulation of an active c-Myc protein does not preclude differentiative events, nor does it override the growth arrest caused by polyamine depletion. These results suggest a new role for polyamines-as negative regulators of c-Myc expression.

3T3 Cells↗
PubMed2000

Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats.

l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis. Adult male Wistar rats were treated with azoxymethane (AOM, 15 mg/kg ip), a chemical carcinogen, once a week for 2 weeks. One week after the second injection the rats were randomly divided into two groups. One group (n = 8) received l-NAME (10 mg/kg body wt/day) in drinking water. The control group (n = 8) received tap water. After 5 weeks, the rats receiving l-NAME showed enhanced mean basal arterial blood pressure, decreased heart rate, and a significant decrease of the cGMP content in the colonic mucosa. In both groups, AOM induced the formation of colonic aberrant crypt foci (ACF). In l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis.

Adenosylmethionine Decarboxylase↗
PubMed2006

Protective effect of gamma-aminobutyric acid (GABA) against cytotoxicity of ethanol in isolated rat hepatocytes involves modulations in cellular polyamine levels.

Gamma-aminobutyric acid (GABA) is considered to be a multifunctional molecule with various physiological effects throughout the body. It is also evident that the liver contains GABA and its transporter. However, the functions of GABA in liver have not been well documented. In this study, the cytoprotective effect of GABA against ethanol-induced hepatotoxicity was evaluated in primary cultured rat hepatocytes. Addition of ethanol induced decrease of cell viability in a dose-dependent manner. However, treatment with GABA resulted in a dose-dependent recovery from ethanol (150 mM)-induced cytotoxicity.GABA reversed the ethanol-induced decrease in intracellular polyamine levels. Furthermore, the addition of polyamines also reversed the ethanol-induced decrease of cell viability. These results suggest that GABA is protective against the cytotoxicity of ethanol in isolated rat hepatocytes and this effect may be modulated by the maintenance of intracellular polyamine levels.

Animals↗
PubMed1992

Inhibition of deoxyribonucleic acid synthesis by difluoromethylornithine. Role of polyamine metabolism in monocrotaline-induced pulmonary hypertension.

Previously, we have shown that the protection provided by 2-difluoromethylornithine (DFMO) against the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) is associated with inhibition of polyamine biosynthesis in the lungs of MCT-treated rats. Although these studies suggest that prevention of the development of MCT-induced PH is polyamine dependent, no one has demonstrated which cellular events of MCT-induced PH are polyamine dependent. In the present study, using DFMO we tested the hypothesis that inhibition of polyamine biosynthesis may protect against MCT-induced PH by limiting increases in DNA synthesis. We injected rats with MCT (60 mg/kg) or 0.9% NaCl and measured DNA synthesis 7 days after MCT by determining [3H]thymidine incorporation into whole lung DNA. We found that 7 days after MCT treatment DNA synthesis was increased compared to the control (0.9% NaCl). However, DFMO treatment (2% in drinking water) reduced the increase in DNA synthesis following MCT. To confirm that DFMO was acting as a specific inhibitor of polyamine biosynthesis in MCT-induced PH, we administered DFMO concurrently with exogenous ornithine (ORN) (2% in drinking water), the substrate for polyamine biosynthesis, to reverse the protection afforded by DFMO against MCT-induced PH. Twenty-one days after MCT injection we examined right ventricular hypertrophy (RVH), mean pulmonary arterial pressure (MPAP), lung wet weight, and lung polyamine levels. While animals given DFMO (MCT + DFMO) did not increase RVH, MPAP, lung wet weight, or lung polyamine levels, animals given ORN (MCT + DFMO + ORN) did develop increases paralleling those found in animals treated with MCT alone. Our results suggest that suppression of polyamine biosynthesis by DFMO may protect against the development of MCT-induced PH in part by preventing increases in DNA synthesis. This suppression of DNA synthesis may limit the proliferation of key lung cells involved in the inappropriate vascular remodelling associated with MCT-induced PH. These results are consistent with our working hypothesis that elevated lung polyamine levels are essential for the development of MCT-induced PH.

Animals↗
PubMed1992

Ornithine decarboxylase induction and polyamine synthesis in the kindling of seizures: the effect of alpha-difluoromethylornithine.

It has been suggested that the kindling of seizures may depend on the induction of genes encoding enzymes involved in neurotransmission. Experimental seizures are followed by an especially rapid and massive induction of brain ornithine decarboxylase (ODC), an enzyme which catalyses the rate-limiting step in the synthesis of polyamines. The latter compounds have been shown to act as positive allosteric modulators of the NMDA receptor, and also to play an important role in cell growth and differentiation. The induction of ODC by seizures has accordingly been suggested to play a pivotal role in the changes in synaptic structure and function that underlie kindling. In the present study we examined the progress of kindling during treatment with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. We found that progressive increase in the duration and severity of kindled seizures and in the duration of local afterdischarges was unaffected by daily injections of DFMO in doses previously shown to cause substantial depression of brain ODC activity. Treatment with DFMO also failed to produce significant anticonvulsant or proconvulsant effects. Progressive increase in seizure activity during kindling is therefore unlikely to depend to any appreciable extent on enhanced synthesis of polyamines by ODC.

Animals↗