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PubMed2003

Ozone impact on the photosynthetic apparatus and the protective role of polyamines.

One of the primary plant mechanisms protecting leaf cells against enhanced atmospheric ozone is the accumulation of polyamines, generally observed as an increase in putrescine level, and in particular its bound form to thylakoid membranes. Ozone-sensitive plants of tobacco (cultivar Bel W3) in contrast to ozone-tolerant Bel B, are not able to increase their endogenous thylakoid membrane-bound putrescine when they are exposed to an atmosphere with enhanced ozone concentration, resulting in reduction of their photosynthetic rates and consequently reduction in plant biomass formation. In comparison to the tolerant cultivar Bel B, a prolongation of ozone exposure thus can lead to typical visible symptoms (necrotic spots) in leaves of the sensitive plant. Exogenously manipulated increase of the cellular putrescine levels of the ozone-sensitive Bel W3 is sufficient to revert these effects, whereas a reduction in endogenous putrescine levels of the tolerant cultivar Bel B renders them sensitive to ozone treatment. The results of this work reveal a regulator role for polyamines in adaptation of the photosynthetic apparatus and consequently to its protection in an environment polluted by ozone.

Biogenic Polyamines↗
PubMed2001

Cloning and characterization of the mouse polyamine-modulated factor-1 (mPMF-1) gene: an alternatively spliced homologue of the human transcription factor.

The natural polyamines and their analogues have been implicated in transcriptional regulation of specific genes. Human polyamine-modulated factor-1 (hPMF-1) was the first polyamine-responsive transcription factor identified. Here the mouse homologue of the hPMF-1 gene is described. Interestingly, the mouse gene (mPMF-1) codes for two alternatively spliced mRNAs. Both of the mouse splice variants, mPMF-1S and mPMF-1L, possess C-terminal coiled-coil domains nearly identical to that found in hPMF-1 and are highly homologous with the human protein. The C-terminal coiled-coil structure is necessary for transcriptional activation. However, the shorter protein, mPMF-1S, does not contain an N-terminal coiled-coil region as do both hPMF-1 and the longer mPMF-1L. mPMF-1L mRNA codes for a protein of 202 amino acids, 37 amino acids longer than the human protein. By contrast, mPMF-1S codes for only 133 amino acids, as a result of two exons being omitted compared with mPMF-1L. Both mouse transcription factors can interact with Nrf-2 (nuclear factor-E2-related factor 2), the normal partner of hPMF-1, substantiating the importance of the C-terminal coiled-coil region responsible for this interaction. Finally, the expression of mPMF-1 is induced when mouse M1 myeloid leukaemia cells are exposed to polyamine analogues, suggesting control similar to that observed for the hPMF-1.

Alternative Splicing↗
PubMed2001

Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation.

Arginase, which exists as the isoforms arginase I and II, catalyzes the hydrolysis of arginine to ornithine and urea. Ornithine is the principal precursor for production of polyamines, which are required for cell proliferation. Rat aortic smooth muscle cells (RASMC) contain constitutive arginase I, and arginase inhibitors cause inhibition of cell proliferation. The objective of this study was to determine whether the elevated expression of arginase I in RASMC causes increased cell proliferation. RASMC were stably transfected with either rat arginase I cDNA or a beta-galactosidase control expression plasmid. Western blots and arginase enzymatic assays revealed high-level expression of cytosolic arginase I in arginase I-transfected RASMC. Moreover, this observation was associated with the increased production of urea and polyamines and higher rates of RASMC proliferation. The two selective inhibitors of arginase, N(G)-hydroxy-l-arginine and S-(2-boronoethyl)-l-cysteine, inhibited arginase and decreased the production of urea and polyamines in arginase I-transfected RASMC, all of which were associated with the inhibition of cell proliferation. This study demonstrates that elevated arginase I expression increases RASMC proliferation by mechanisms involving increased production of polyamines. These observations suggest that arginase I plays a potentially important role in controlling RASMC proliferation.

Animals↗
PubMed2003

Peach (Prunus persica L.) fruit growth and ripening: transcript levels and activity of polyamine biosynthetic enzymes in the mesocarp.

Transcript levels and activities of the polyamine biosynthetic enzymes arginine decarboxylase (ADC, EC 4.1.1.19), ornithine decarboxylase (ODC, EC 4.1.1.17) and S-adenosylmethionine decarboxylase (SAMDC, EC 4.1.1.21), as well as free polyamine titres, were analysed throughout the four growth stages S1-S4 leading up to ripening in the mesocarp from peach fruit (Prunus persica L. Batsch cv. Redhaven) grown under field conditions. SAMDC mRNA, which was northern analysed by using a PCR-generated homologous SAMDC probe, and ADC mRNA levels appeared quite stable during fruit development, while ODC transcript accumulation showed a discontinuous trend. The pattern of transcript levels during growth did not correlate with that of the relative enzyme activity, which instead correlated well with free polyamine levels. Both exhibited maximum levels in S1 and a smaller peak in S3. The behaviour of the polyamine biosynthetic machinery is discussed in relation to the different cell growth rates occurring during fruit development.

Adenosylmethionine Decarboxylase↗
PubMed1992

Effect of the beta-adrenoceptor agonist clenbuterol and phytohaemagglutinin on growth, protein synthesis and polyamine metabolism of tissues of the rat.

1. The kidney bean lectin, phytohaemagglutinin (PHA), induced a marked atrophy of skeletal muscle which was evident from the changes in tissue composition (protein, RNA, DNA and polyamine content) and from the reduction in weight and protein synthesis of hind leg muscles of rats fed on kidney bean-diets for four days. The beta-adrenoceptor agonist, clenbuterol, induced skeletal muscle hypertrophy by transiently stimulating protein synthesis. As a consequence, the muscle loss caused by a short exposure to PHA was, in part, ameliorated by clenbuterol treatment. 2. Cardiac muscle was affected to a lesser extent than skeletal muscle by both clenbuterol and the lectin. However, there was evidence that protein synthesis in heart was reduced by PHA. 3. PHA had opposite effects on the gut, the lectin-induced hyperplasia of the jejunum was accompanied by a large increase in protein synthesis. Clenbuterol alone had no effect on the jejunum whereas a combination of PHA and clenbuterol appeared to exacerbate the effect of the lectin on gut. 4. Both the lectin-induced gut growth and the hypertrophy of skeletal muscle caused by clenbuterol were preceded by the accumulation of polyamines in the respective tissues. Of particular note was the observation that a significant increase in the proportion of the intraperitoneally injected 14C-labelled spermidine or putrescine taken up by the growing tissues could be detected by the second day. Therefore, the measurement of uptake of labelled polyamines may be used as a sensitive indicator of early alterations in tissue metabolism.

Animals↗
PubMed2003

Prevention of TNF-alpha-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2.

It has been documented that polyamines play a critical role in the regulation of apoptosis in intestinal epithelial cells. We have recently reported that protection from TNF-alpha/cycloheximide (CHX)-induced apoptosis in epithelial cells depleted of polyamines is mediated through the inactivation of a proapoptotic mediator, JNK. In this study, we addressed the involvement of the MAPK pathway in the regulation of apoptosis after polyamine depletion of IEC-6 cells. Polyamine depletion by alpha-difluromethylornithine (DFMO) resulted in the sustained activation of ERK in response to TNF-alpha/CHX treatment. Pretreatment of polyamine-depleted IEC-6 cells with a cell membrane-permeable MEK1/2 inhibitor, U-0126, significantly inhibited TNF-alpha/CHX-induced ERK phosphorylation and significantly increased DNA fragmentation, JNK activity, and caspase-3 activity in response to TNF-alpha/CHX. Moreover, the dose dependency of U-0126-mediated inhibition of TNF-alpha/ CHX-induced ERK phosphorylation correlated with the reversal of the antiapoptotic effect of DFMO. IEC-6 cells expressing constitutively active MEK1 had decreased TNF-alpha/CHX-induced JNK phosphorylation and were significantly protected from apoptosis. Conversely, a dominant-negative MEK1 resulted in high basal activation of JNK, cytochrome c release, and spontaneous apoptosis. Polyamine depletion of the dominant-negative MEK1 cells did not prevent JNK activation or cytochrome c release and failed to confer protection from both TNF-alpha/CHX and camptothecin-induced apoptosis. Finally, expression of a dominant-negative mutant of JNK significantly protected IEC-6 cells from TNF-alpha/CHX-induced apoptosis. These data indicate that polyamine depletion results in the activation of ERK, which inhibits JNK activation and protects cells from apoptosis.

Animals↗
PubMed2005

Significance of targeting polyamine metabolism as an antineoplastic strategy: unique targets for polyamine analogues.

The polyamines, putrescine, spermidine, and spermine, are naturally occurring polycationic alkylamines that are absolutely required for eukaryotic cell growth. Importantly, the polyamine metabolic pathway, as well as the requirement of polyamines for cell growth, is frequently dysregulated in cancer cells, thus providing a unique set of targets for therapeutic intervention. Ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, is frequently up-regulated in preneoplastic cells, and has been implicated as an oncogene in multiple tumor types. Several model systems have demonstrated that inhibition of ODC's enzymatic activity and down-regulation of its expression are rational strategies for both chemotherapy and chemoprevention. Specific inhibitors of ODC, most notably 2-difluoromethylornithine (DFMO), have been used experimentally to validate polyamine metabolism as an antineoplastic strategy. However, multiple biochemical and clinical limitations to these ODC-targeting strategies minimize their value as therapeutic tools. Included among these limitations are poor bioavailability of the inhibitor, and the compensatory up-regulation of polyamine metabolism and transport that allow tumor cells to escape the growth inhibitory effects of blockers specifically targeting ODC. As a strategy to overcome the limitations of direct enzyme inhibition, several groups have pursued the design of polyamine analogues that specifically target the dysregulated polyamine metabolism found in tumors. These analogues have been developed specifically to target the specific polyamine transporter, thus competing with circulating natural polyamines. Additionally, most of the analogues examined thus far maintain the regulatory function of the natural polyamines, but are unable to functionally substitute for them in promoting growth. Specifically, individual analogues have demonstrated the ability to down-regulate each of the biosynthetic enzymes without causing compensatory increases in parallel systems or increases in polyamine uptake. Additionally, specific analogues produce tumor specific up regulation of the rate-limiting enzymes in polyamine catabolism. These results are particularly significant in that the products of polyamine catabolism, including H2O2, have been demonstrated to participate in the tumoricidal activity of specific analogues.

Animals↗
PubMed1990

[Detection of polyamines by a new enzymatic differential assay. (8) Studies on tissue polyamine concentrations in patients with genitourinary malignant diseases].

Polyamine concentrations of human cancerous and non-cancerous tissues from the kidney, ureter, bladder were measured by a new enzymatic method for isolation and determination of polyamines. In cancerous and non-cancerous tissue of the organs studied, the spermine level was highest followed by the spermidine and diamine levels. The concentrations of diamine, spermidine and spermine in cancerous tissues were significantly higher than those in non-cancerous tissues, but there was no significant difference in the spermidine/spermine ratio between the cancerous and non-cancerous tissues. These data suggest that polyamines are produced above the normal levels in pathological conditions such as renal cell carcinoma, ureteral cancer and bladder cancer.

Biogenic Polyamines↗
PubMedDate not supplied

Selectivity of polyamine involvement in hormone action on normal and neoplastic target tissues of the rat.

The present experiments were designed to evaluate the polyamine involvement in hormonal actions on proliferation and receptor content of neoplastic tissue (hormone-responsive breast cancer) as well as on growth of normal endocrine target tissue (uterus) in the same animals. Administration of estradiol and perphenazine (to stimulate endogenous prolactin release) stimulated N-nitrosomethyl-urea (NMU)-induced rat mammary tumor growth following ovariectomy-induced tumor regression. Such hormonal activation of breast cancer growth was completely abolished by treatment with alpha-difluoromethyl-ornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, which lowered tumor content of polyamines. The growth inhibitory effect of DFMO was partially reversible by exogenous putrescine administration. In contrast, the rise in cytosolic content of progesterone receptors induced by hormonal treatment was not affected by suppression of tumor polyamine levels by DFMO. Similarly, DFMO administration failed to influence the hormone-induced increase in uterine weight in the same animals. Thus, our data suggest selectivity of polyamine involvement in hormone actions, which, in our experimental system, seems to be restricted to the endocrine control of neoplastic cell proliferation.

Animals↗
PubMed1992

Indirect photometric detection of polyamines in biological samples separated by high-performance capillary electrophoresis.

A rapid separation of polyamines and some related amino acids in cultured tumor cells by high-performance capillary zone electrophoresis with indirect photometric detection is demonstrated. 60 cm x 75 microns I.D. fused-silica capillary was used for the separation and quinine sulfate was used as a background electrolyte (BGE). Several polyamines (putrescine, spermidine and spermine), amino acids (lysine, arginine, histidine) and simple cations (K+, Na+) were easily separated in less than 10 min. Using the indirect photometric detection method, femtomole amounts of polyamines extracted from the tumor cells were detected from nanoliter injection volumes, and the signal response was linear over two orders of magnitude.

Animals↗
PubMed1991

Glutamate and glycine co-activate while polyamines merely modulate the NMDA receptor complex.

1. Agonists may act at any one of three sites on the N-methyl-D-aspartate (NMDA) receptor-effector complex to promote opening of the associated ion channel. The three sites are activated by i) NMDA, L-glutamate, aspartate, and other dicarboxylic amino acids; ii) glycine, D-serine, D-cycloserine, and others; iii) the polyamines spermine or spermidine, but not cadaverine or putrescine. 2. This opening by exogenous agonists is reflected by an enhanced binding of the phencyclidine-like dissociative anesthetic [3H]MK-801 to rat cortical membranes (well washed to remove endogenous agonists, e.g., L-glutamate, glycine). 3. The effects of adding combinations of agonists yielded stimulation approximately equal to the sum of each agonist's effect, suggesting that in the first approximation the three classes act at independent sites. 4. When the glutamate (E) site was antagonized with D-2-amino-5-phosphonopentanoate (D-AP5), no stimulation in binding could be elicited by agonists at the two other sites. Activation of the E site is therefore necessary but not sufficient for channel opening. 5. When the glycine (G) site was antagonized with 7-chlorokynurenate, no stimulation in binding could be elicited by agonists at the other two sites. Activation of the G site is therefore necessary but not sufficient for channel opening. 6. Of the two putative antagonists for the polyamine (PA) site, ifenprodil fails to completely inhibit the binding of [3H]MK-801, whereas arcaine inhibited [3H]MK-801 binding completely. We present data which question the selectivity of arcaine for the polyamine site, and propose that the polyamine site is merely modulatory, but neither necessary nor sufficient, for channel opening.

2-Amino-5-phosphonovalerate↗
PubMed2005

Oxidative metabolites are involved in polyamine-induced microglial cell death.

Pathological activation of microglia, which reside quiescently in physiological CNS, is associated with various neurodegenerative diseases. Endogenous polyamines, spermidine and spermine, are known to be activators of cell proliferation and differentiation. We previously reported that both spermidine and spermine induce dose-dependent cell death in cultured rat brain microglia at a submicromolar concentration range via apoptotic process, whereas cultured astrocytes were less sensitive to these polyamines [Neuroscience 120 (2003) 961]. These polyamine effects were observed only in the presence of fetal bovine serum. In the present study we examined further the mechanism of polyamine-induced microglial cell death. Amine oxidase in fetal bovine serum produces hydrogen peroxide and an aminoaldehyde from spermine, and the latter generates acrolein spontaneously. Acrolein was found to be much more toxic to microglia than to astrocytes and the effective concentration of acrolein was similar to that of spermine, whereas hydrogen peroxide was marginally toxic. Aminoguanidine, an inhibitor of amine oxidase, blocked the toxic effects of spermine on microglia. Spermine cytotoxicity was also prevented by antioxidant reagents; glutathione (reduced form), cysteine, and N-acetylcysteine. These results suggest that polyamine-induced apoptotic cell death of microglia is triggered by an oxidative stress with acrolein, which is produced by amine oxidase from polyamine. The different toxicities of polyamine between two glial cells may regulate the balance of glial activation in some pathological conditions of CNS.

Acrolein↗
PubMed1998

Arginine decarboxylase (polyamine synthesis) mutants of Arabidopsis thaliana exhibit altered root growth.

Putrescine and polyamines are produced by two alternative pathways in plants. One pathway starts with the enzyme arginine decarboxylase; the other with ornithine decarboxylase. The authors developed an in vivo screening strategy to identify mutants with low levels of arginine decarboxylase activity. The screen requires both a primary screen of the M2 generation and a secondary screen of the M3 generation. The method used was to screen 15,000 EMS-mutagenized M2 seedlings for low levels of arginine decarboxylase (ADC) activity and identified seven mutants that fall into two complementation groups. These mutants have from 20% to 50% of wild-type enzyme activity. Morphological alterations common among the mutants include increased levels of lateral root branching. The authors obtained a double mutant combining the alleles with the lowest activities from the two complementation groups; this has lower ADC enzyme activity and putrescine levels than either of the single mutants. The double mutant has highly kinked roots that form a tight cluster; it also has narrower leaves, sepals, and petals than either single mutant or wild-type, and delayed flowering. These results suggest there may be more than one ADC gene in Arabidopsis, and that ADC and polyamine levels play roles in root meristem function and in lateral growth of leaf-homolog organs.

Alleles↗
PubMed2000

Polyamine uptake in cultured astrocytes: characterization and modulation by protein kinases.

The properties and regulation of the polyamine transport system in brain are still poorly understood. The present study shows, for the first time, the existence of a polyamine transport system in cerebellar astrocytes and suggests that polyamine uptake is mediated by a single and saturable high-affinity transport system for putrescine, spermine, and spermidine (K:(m) = 3.2, 1.2, and 1.8 microM:, respectively). Although substitution of NaCl by choline chloride produced a decrease in the putrescine, spermine, and spermidine uptake, it seems that polyamine transport in cerebellar astrocytes is not mediated by an Na(+) cotransport as in the presence of Na(+) and cholinium, polyamine uptake was much lower than when measured in a sucrose-based medium. On the other hand, ouabain, gramicidin (a Na(+) ionophore), and ionomycin (a Ca(2+) ionophore) produced a strong inhibition of polyamine uptake, suggesting that membrane potential could have an important role in the functioning of the astroglial polyamine uptake system. Moreover, protein kinase C inhibition produced an enhancement of polyamine uptake, whereas stimulation of protein kinase C with phorbol esters inhibited polyamine uptake. Alternatively, the tyrosine kinase inhibitor genistein caused a marked reduction in the uptake. No effects on polyamine uptake were observed with inhibitors and activators of cyclic AMP-dependent protein kinase or when Ca(2+)/calmodulin-dependent protein kinase II was inhibited with KN-62. These results suggest that the polyamine uptake system in cerebellar astrocytes could be modulated by protein kinase C and tyrosine kinase activities.

Animals↗
PubMed1998

Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder.

The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.

Adenosylmethionine Decarboxylase↗
PubMed1989

Effects of dietary polyamine precursors on the metabolism and tissue concentrations of amino acids in the rat.

Experiments were conducted to determine the effects of dietary supplements of amino acid precursors of polyamines on amino acid metabolism in the rat in order to better understand comparative aspects of polyamine metabolism. Rats were fed isonitrogenous combinations of methionine, ornithine, arginine and 2-difluoromethylornithine in casein-based diets. It was observed that hepatic concentrations of methionine, 5'-deoxy-5'-methylthioadenosine and decarboxylated S-adenosylmethionine were more easily influenced by diet than were arginine and metabolites. It was concluded that rats may be more refractory to exogenous polyamine precursor amino acids than are chicks because of the presence of a functional urea cycle.

Adenosine↗
PubMed1990

Polyamine metabolism and uptake during Phaseolus vulgaris lectin, PHA-induced growth of rat small intestine.

Kidney bean lectin, PHA, stimulated the hyperplastic and hypertrophic growth of rat small intestine. This growth was preceded by a rapid accumulation of polyamines in the small intestine. However, since the lectin had little effect on in situ polyamine biosynthesis, most of the polyamines must have been of extracellular origin. To investigate the source of polyamines, both the luminal uptake and basolateral transport of polyamines by the rat small intestine were measured in vivo. Luminal polyamine uptake was apparently by passive diffusion, non-saturable, linearly dependent on concentration and its extent was not stimulated by PHA. In contrast, 14C-polyamines injected intraperitoneally were probably taken up by a transport system(s). Moreover, basolateral polyamine transport was stimulated in a time-dependent manner when small intestinal growth was stimulated by PHA. However, in keeping with the finding of polyamine accumulation prior to demonstrable growth of the tissue, stimulation by PHA of the polyamine transport system also preceded small intestinal growth. Stimulation of polyamine transport by luminal factors is possibly a general mechanism involved in intestinal adaptation.

Adaptation, Physiological↗
PubMed1992

Polyamines as a chemotaxonomic marker in bacterial systematics.

Aliphatic linear polyamines, from diamines to hexaamines, tertiary branched tetraamines, and quaternary branched pentaamines are widely distributed in eubacteria, archaebacteria, and cyanobacteria. Twenty-four linear types and four branched types are acid extractable from bacterial cells and can be chromatographically analyzed and identified. The varieties of polyamines are due to the combination of amino acid decarboxylase activities to form diamines, aminopropyl- and aminobutyl-transfer activities mediated by aminopropyltransferases or Schiff-base complex formation, and hydroxylation activity. The absence or presence of spermidine, norspermidine or homospermidine and the occurrence of 2-hydroxyputrescine and diaminopropane are related to grouping into the alpha, beta, gamma, and delta subclasses within Proteobacteria. Flavobacterium complex and green bacteria contain putrescine and homospermidine. Gram-negative thermophiles contain long linear and branched polyamines; however, their distribution profiles are species specific. Gram-positive eubacteria, which comprise Bacillus cluster, anaerobes, and actinomycetes, ubiquitously contain putrescine and spermidine, while the occurrence of spermine is limited to thermophiles. Archaebacteria are separated into polyamine-absent methanogens and halophiles, homospermidine-dominant methanogens, spermidine-dominant methanogens, and spermidine- and norspermidine-containing thermophiles. Cyanobacteria comprise two types; one group contains homospermidine and the other spermidine. The polyamine distribution pattern can serve as a chemotaxonomic marker in bacterial classification and is associated with bacterial systematics on the level of order, family, or genus.

Bacteria↗