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PubMed1997

Polyamines regulate both transcription and translation of the gene encoding ornithine decarboxylase antizyme in mouse.

The degradation of ornithine decarboxylase (ODC) is mediated by antizyme, a protein regulated by the end-products of ODC activity, the polyamines. High levels of polyamines induce a +1 ribosomal frameshift in the translation of the rat antizyme message leading to the expression of a full-length protein. We have studied whether the regulation of antizyme expression occurs only at the level of translation or whether polyamine levels also affect the transcription of the antizyme gene. Thus, we have cloned and sequenced the mouse homologues of the rat ODC-antizyme gene and cDNA. Northern blot analysis shows that although high concentrations of polyamines do not affect the steady-state levels of antizyme message in L1210 leukemia cells, polyamine depletion using 2-(difluoromethyl)ornithine [Orn(F2Me)] leads to a marked decrease in mRNA levels. Results of transient transfections of luciferase-reporter-gene constructs driven by antizyme promoter fragments in untreated and Orn(F2Me)-treated Balb/C 3T3 cells indicate that the transcription of the antizyme gene is altered upon polyamine depletion. The amount of antizyme protein on Western blots was also altered by polyamine depletion and addition, and the polysomal distribution of antizyme message suggests a general translational increase of the message when polyamine concentrations are high. These results indicate a role for polyamines in the transcriptional and translational regulation of ornithine decarboxylase antizyme.

Animals↗
PubMed2006

Polyamines as an inhibitor on erythropoiesis of hemodialysis patients by in vitro bioassay using the fetal mouse liver assay.

The pathogenesis of anemia in patients with chronic renal failure has been greatly attributed to erythropoietin (EPO) deficiency. Recently, however, there has been some thought that uremic inhibitors might suppress the activity of EPO and reduce the maturation of erythropoiesis. Polyamines are well known to be involved in the regulation of cellular proliferation and differentiation. Furthermore, the polyamine levels in the serum or erythrocytes are elevated in chronic hemodialysis patients, and can be lowered immediately by hemodialysis. In the present study, we first measured the polyamines levels (putrescine, spermidine, spermine) by high performance liquid chromatography (HPLC) in 20 chronic hemodialysis patients, and investigated the effects of polyamines on erythropoiesis by in vitro bioassay using fetal mouse liver cells. The direct effects of polyamines in erythroid colony formation in the medium with and without EPO were evaluated. Each polyamine level in chronic hemodialysis patients was higher than in the healthy subjects, and a significant negative correlation was found between polyamines and erythropoiesis. Polyamines inhibited the activity of EPO, but they did not have any direct effect on colony formation of the fetal mouse liver cells. These results suggest that polyamines have inhibitory effects on the proliferation or maturation of erythroid precursor cells and are intimately involved in the pathogenesis of renal anemia in chronic hemodialysis patients.

Adolescent↗
PubMed2007

Enhancement of the synthesis of RpoN, Cra, and H-NS by polyamines at the level of translation in Escherichia coli cultured with glucose and glutamate.

Proteins whose synthesis is enhanced by polyamines at the level of translation were identified in a polyamine-requiring mutant cultured in the presence of 0.1% glucose and 0.02% glutamate instead of 0.4% glucose as an energy source. Under these conditions, enhancement of cell growth by polyamines was almost the same as that in the presence of 0.4% glucose. It was found that synthesis of RpoN, Cra, and H-NS was enhanced by polyamines at the level of translation at the early logarithmic phase of growth (A(540) of 0.15). The effects of polyamines on synthesis of RpoN, H-NS, and Cra were due to the existence of unusual Shine-Dalgarno sequences (RpoN and H-NS) and an inefficient GUG initiation codon (Cra) in their mRNAs. Thus, rpoN, cra, and hns genes were identified as new members of the polyamine modulon. Because most of the polyamine modulon genes thus far identified encode transcription factors (RpoS [sigma(38)], Cya, FecI [sigma(18)], Fis, RpoN [sigma(54)], Cra, and H-NS), DNA microarray analysis of mRNA expressed in cells was performed. At the early logarithmic phase of growth, a total of 97 species of mRNAs that were up-regulated by polyamines more than twofold were under the control of seven polyamine modulon genes mentioned above.

Bacterial Proteins↗
PubMed1987

Mucosal polyamine profile in normal and adapting (hypo and hyperplastic) intestine: effects of DFMO treatment.

The polyamines, putrescine, spermidine, and spermine, are believed to play an important role in modulating normal and adaptive intestinal mucosal growth. Polyamine synthesis is rate limited by ornithine decarboxylase (ODC) and ODC activity is specifically inhibited by -difluoromethyl ornithine (DFMO). To assess the importance of polyamines in adaptive growth we first measured mucosal polyamine profiles at different sites in the normal rat intestine and compared the results with those obtained in adaptive hypoplasia (seven days parental nutrition, TPN), in the adaptive hyperplasia of two weeks after 90% small bowel resection (SBR) or pancreatico biliary diversion (PBD). We then examined the effects of DFMO (2% in drinking water, daily from two days before surgery) on the polyamine concentrations and the adaptive response to PBD. The hyperplasia of SBR and PBD was associated with increases in all the polyamine concentrations particularly putrescine. TPN induced a modest degree of hypoplasia and little change in polyamine synthesis resulting in subnormal polyamine concentrations and significantly inhibited the mucosal adaptive response. Changes in polyamine metabolism are important in intestinal mucosal adaptation and by controlling these changes adaptive growth can be controlled.

Adaptation, Physiological↗
PubMed2003

Regulation of adherens junctions and epithelial paracellular permeability: a novel function for polyamines.

Maintenance of intestinal mucosal epithelial integrity requires polyamines that are involved in the multiple signaling pathways controlling gene expression and different epithelial cell functions. Integrity of the intestinal epithelial barrier depends on a complex of proteins composing different intercellular junctions, including tight junctions, adherens junctions, and desmosomes. E-cadherin is primarily found at the adherens junctions and plays a critical role in cell-cell adhesions that are fundamental to formation of the intestinal epithelial barrier. The current study determined whether polyamines regulate intestinal epithelial barrier function by altering E-cadherin expression. Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) reduced intracellular free Ca2+ concentration ([Ca2+]cyt), decreased E-cadherin expression, and increased paracellular permeability in normal intestinal epithelial cells (IEC-6 line). Polyamine depletion did not alter expression of tight junction proteins such as zona occludens (ZO)-1, ZO-2, and junctional adhesion molecule (JAM)-1. Addition of exogenous polyamine spermidine reversed the effects of DFMO on [Ca2+]cyt and E-cadherin expression and restored paracellular permeability to near normal. Elevation of [Ca2+]cyt by the Ca2+ ionophore ionomycin increased E-cadherin expression in polyamine-deficient cells. In contrast, reduction of [Ca2+]cyt by polyamine depletion or removal of extracellular Ca2+ not only inhibited expression of E-cadherin mRNA but also decreased the half-life of E-cadherin protein. These results indicate that polyamines regulate intestinal epithelial paracellular barrier function by altering E-cadherin expression and that polyamines are essential for E-cadherin expression at least partially through [Ca2+]cyt.

Adherens Junctions↗
PubMed2005

Polyamine depletion induces nucleophosmin modulating stability and transcriptional activity of p53 in intestinal epithelial cells.

Our previous studies have shown that polyamines are required for normal intestinal mucosal growth and that decreased levels of polyamines inhibit intestinal epithelial cell (IEC) proliferation by stabilizing p53 and other growth-inhibiting proteins. Nucleophosmin (NPM) is a multifunctional protein that recently has been shown to regulate p53 activity. In the present study, we sought to determine whether polyamine depletion increases NPM modulating the stability and transcriptional activity of p53 in a normal IEC-6 intestinal epithelial cell line. Depletion of cellular polyamines by alpha-difluoromethylornithine, the specific inhibitor of polyamine biosynthesis, stimulated expression of the NPM gene and induced nuclear translocation of NPM protein. Polyamine depletion stimulated NPM expression primarily by increasing NPM gene transcription and its mRNA stability, and it induced NPM nuclear translocation through activation of phosphorylation of mitogen-activated protein kinase kinase. Increased NPM interacted with p53 and formed a NPM/p53 complex in polyamine-deficient cells. Inhibition of NPM expression by small interfering RNA targeting NPM (siNPM) not only destabilized p53 as indicated by a decrease in its protein half-life but also prevented the increased p53-dependent transactivation as shown by suppression of the p21 promoter activity. Decreased expression of NPM by siNPM also promoted cell growth in polyamine-deficient cells. These results indicate that 1) polyamine depletion increases expression of the NPM gene and enhances NPM nuclear translocation and 2) increased NPM interacts with and stabilizes p53, leading to inhibition of IEC-6 cell proliferation.

Active Transport, Cell Nucleus↗
PubMed2004

MEK1 restores migration of polyamine-depleted cells by retention and activation of Rac1 in the cytoplasm.

We previously showed that polyamines are required for proliferation and migration both in vivo and in a cultured intestinal epithelial cell (IEC-6) model. Wounding of the IEC-6 monolayer induced transient ERK activation, which was further enhanced by EGF. EGF stimulated migration in control and polyamine-depleted cells, but the degree of stimulation was significantly less in polyamine-depleted cells. Inhibition of MEK1 inhibited basal as well as EGF-induced ERK activation and migration. Expression of constitutively active (CA)-MEK and dominant-negative (DN)-MEK had significant effects on F-actin structure. CA-MEK increased stress fiber and lamellipodia formation, while DN-MEK showed loss of stress fibers and abnormal actin cytoskeletal structure. Unlike EGF, CA-MEK significantly increased migration of both control and polyamine-depleted cells. The most important and significant finding in this study was that polyamine depletion caused localization of Rac1 and RhoA to the nuclear as well as perinuclear regions. Interestingly, CA-MEK completely reversed the subcellular distribution of Rac1 and RhoA proteins in polyamine-depleted cells. Polyamine depletion increased Rac1 in the nuclear fraction and decreased it in the cytoplasmic and membrane fractions of vector-transfected cells. CA-MEK prevented accumulation of Rac1 in the nucleus. Polyamine depletion significantly decreased Rac1 activity during 6-h migration in vector-transfected cells. Cells transfected with CA-MEK had almost identical levels of activated Rac1 in all three groups. These results suggest that polyamine depletion prevents activation of Rac1 and RhoA by sequestering them to the nucleus and that expression of constitutively active MEK reverses this effect, creating the cellular localization required for activation.

Animals↗
PubMed2004

Polyamine-modulated expression of c-myc plays a critical role in stimulation of normal intestinal epithelial cell proliferation.

The nuclear protein c-Myc is a transcription factor involved in the control of cell cycle. Our previous studies indicated that cellular polyamines are absolutely required for cell proliferation in crypts of small intestinal mucosa and that polyamines have the ability to stimulate expression of the c-myc gene. The current study went further to determine whether induced nuclear c-Myc plays a role in stimulation of cell proliferation by polyamines in intestinal crypt cells (IEC-6 line). Exposure of normal quiescent cells after 24-h serum deprivation to 5% dialyzed fetal bovine serum (dFBS) increased both cellular polyamines and expression of the c-myc gene. Increased c-Myc protein formed heterodimers with its binding partner, Max, and specifically bound to the Myc/Max binding site, which was associated with an increase in DNA synthesis. Depletion of cellular polyamines by pretreatment with alpha-difluoromethylornithine (DFMO) prevented increases in c-myc expression and DNA synthesis induced by 5% dFBS. c-Myc gene transcription and cell proliferation decreased in polyamine-deficient cells, whereas the natural polyamine spermidine given together with DFMO maintained c-myc gene expression and cell growth at normal levels. Disruption of c-myc expression using specific c-myc antisense oligomers not only inhibited normal cell growth (without DFMO) but also prevented the restoration of cell proliferation by spermidine in polyamine-deficient cells. Ectopic expression of wild-type c-myc by recombinant adenoviral vector containing c-myc cDNA increased cell growth. These results indicate that polyamine-induced nuclear c-Myc interacts with Max, binds to the specific DNA sequence, and plays an important role in stimulation of normal intestinal epithelial cell proliferation.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed1990

Role of polyamines in mitogenic and secretory responses of pancreatic beta-cells to growth factors.

We have investigated the effects of glucose and the polypeptide growth factor growth hormone (GH), platelet-derived growth factor (PDGF), insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor alpha (TGF alpha) on the polyamine content, in relation to proliferation and insulin secretion and content, of pancreatic beta-cells. Fetal rat pancreatic islets containing a high proportion of beta-cells were cultured for 3 days with growth factors. beta-cell replication was significantly increased by glucose, GH, and PDGF plus IGF-I in parallel with increased islet polyamine contents. In contrast, neither EGF nor TGF alpha influenced the islet DNA synthesis rate, polyamine content, insulin content, or insulin accumulation in culture medium. When the increased polyamine content evoked by growth-promoting agents was prevented by inhibitors of polyamine synthesis, elevated DNA synthesis rates persisted or were even augmented. However, subcellular fractionation analysis of islet homogenates revealed that the nuclear polyamine content was not affected by the inhibitors. On the other hand, islet insulin content and glucose-regulated insulin release were decreased by polyamine synthesis inhibitors. Glucose oxidation rates remained unchanged, suggesting that inhibitors were not toxic to islet cells. We conclude that prevention of increases in total cellular content of polyamines in response to glucose, GH, or PDGF plus IGF-I does not prevent mitogenicity of these growth factors. However, when their synthesis is inhibited normal levels of polyamines seem to be maintained in the cell nucleus, an event that may be sufficient to permit a mitotic signal to be translated into a proliferative response.

Animals↗
PubMed1994

Polyamines influence transglutaminase activity and cell migration in two cell lines.

Transglutaminases (TGAs) catalyze the cross-linking of proteins through formation of gamma-glutaminyl-epsilon-lysine bonds and incorporation of small-molecular-weight amines, including polyamines, into the gamma-glutamine sites of proteins. Tissue TGA has been shown to establish covalent cross-links between cytoskeletal proteins using polyamines as substrates, and protein-polyamine conjugates have been identified in a variety of cells. We have shown previously that polyamines are required for cell migration in IEC-6 cells [S. A. McCormack, M. J. Viar, and L. R. Johnson. Am. J. Physiol. 264 (Gastrointest. Liver Physiol. 27): G367-G374, 1993]. In this study, we explored the relationship between cell migration, polyamines, and tissue TGA activity in two cell lines and found that while both IEC-6 and Caco-2 cells required normal levels of polyamines to migrate across a denuded surface, tissue TGA activity responded differently to polyamine deficiency brought about by treatment with alpha-difluoromethylornithine (DFMO). DFMO is a specific and irreversible inhibitor of ornithine decarboxylase, a rate-limiting enzyme of polyamine biosynthesis. In IEC-6 cells, tissue TGA activity decreased significantly with DFMO treatment concurrent with a rise in inactive TGA protein as measured by Western blot analysis. On the other hand, in Caco-2 cells, tissue TGA activity and protein increased significantly with DFMO treatment. In both cell lines, addition of polyamines to the DFMO treatment restored cell migration, tissue TGA activity, and protein to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Polyamines modulate transcription but not posttranscription of c-myc and c-jun in IEC-6 cells.

The goal of the current study was to examine whether polyamines are involved in the regulation of transcription and posttranscription of the protooncogenes c-myc and c-jun in intestinal epithelial cells. Studies were conducted in the IEC-6 cell line derived from rat small intestinal crypt cells. Administration of alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine synthesis, for 4 or 6 days not only almost completely depleted total (whole) cellular and nuclear polyamines but also significantly decreased expression of the protooncogenes c-myc and c-jun in IEC-6 cells. Using nuclear run-on transcription assay, we demonstrated that the basal rate of transcription of c-myc was decreased by 55% at 4 days and by 60% at 6 days in the DFMO-treated cells. The c-jun transcription in DFMO-treated cells was decreased by 75% at 4 days and 85% at 6 days. The transcription rates of c-myc and c-jun were dramatically stimulated by 5% dialyzed fetal bovine serum (dFBS) in normal quiescent cells. However, polyamine depletion significantly prevented the increased transcription of these two genes in the DFMO-treated cells exposed to 5% dFBS. Furthermore, direct administration of spermidine to isolated nuclei from polyamine-deficient (caused by DFMO) cells resulted in a 2- to 2.5-fold increase in c-myc and c-jun transcription. There were no significant changes in the half-lives of c-myc and c-jun mRNAs between the controls and the DFMO-treated cells. These results indicate that 1) polyamines are required for the transcription of the protooncogenes c-myc and c-jun in IEC-6 cells and 2) depletion of intracellular polyamines has no effect on posttranscriptional regulation of c-myc and c-jun mRNAs. These findings suggest that polyamines play an important role in the regulation of the transcription of protooncogenes, and this may be one mechanism by which polyamines modulate mucosal cell division.

Animals↗
PubMed1999

Inhibition of polyamine synthesis induces p53 gene expression but not apoptosis.

The nuclear phosphoprotein p53 acts as a transcription factor and is involved in growth inhibition and apoptosis. The present study was designed to examine the effect of decreasing cellular polyamines on p53 gene expression and apoptosis in small intestinal epithelial (IEC-6) cells. Cells were grown in DMEM containing 5% dialyzed fetal bovine serum in the presence or absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, for 4, 6, and 12 days. The cellular polyamines putrescine, spermidine, and spermine in DFMO-treated cells decreased dramatically at 4 days and remained depleted thereafter. Polyamine depletion by DFMO was accompanied by a significant increase in expression of the p53 gene. The p53 mRNA levels increased 4 days after exposure to DFMO, and the maximum increases occurred at 6 and 12 days after exposure. Increased levels of p53 mRNA in DFMO-treated cells were paralleled by increases in p53 protein. Polyamines given together with DFMO completely prevented increased expression of the p53 gene. Increased expression of the p53 gene in DFMO-treated cells was associated with a significant increase in G1 phase growth arrest. In contrast, no features of programmmed cell death were identified after polyamine depletion: no internucleosomal DNA fragmentation was observed, and no morphological features of apoptosis were evident in cells exposed to DFMO for 4, 6, and 12 days. These results indicate that 1) decreasing cellular polyamines increases expression of the p53 gene and 2) activation of p53 gene expression after polyamine depletion does not induce apoptosis in intestinal crypt cells. These findings suggest that increased expression of the p53 gene may play an important role in growth inhibition caused by polyamine depletion.

Animals↗
PubMed2003

Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells.

Smad proteins are transcription activators that are critical for transmitting transforming growth factor-beta (TGF-beta) superfamily signals from the cell surface receptors to the nucleus. Our previous studies have shown that cellular polyamines are essential for normal intestinal mucosal growth and that a decreased level of polyamines inhibits intestinal epithelial cell proliferation, at least partially, by increasing expression of TGF-beta/TGF-beta receptors. The current study went further to determine the possibility that Smads are the downstream intracellular effectors of activated TGF-beta/TGF-beta receptor signaling following polyamine depletion. Studies were conducted in IEC-6 cells derived from rat small intestinal crypts. Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity. Polyamine depletion-induced Smads were also associated with a significant increase in transcription activation as measured by luciferase reporter gene activity of Smad-dependent promoters. Inhibition of Smads by a dominant-negative mutant Smad4 in the DFMO-treated cells prevented the increased Smad transcription activation. Polyamine-deficient cells highly expressed TGF-beta and were growth-arrested at the G1 phase. Inhibition of TGF-beta by treatment with either immunoneutralizing anti-TGF-beta antibody or TGF-beta antisense oligodeoxyribonucleotides not only blocked the induction of Smad activity but also decreased the Smad-mediated transcriptional activation in polyamine-depleted cells. These findings suggest that Smads are involved in the downstream cellular processes mediated by cellular polyamines and that increased TGF-beta/TGF-beta receptor signaling following polyamine depletion activates Smads, thus resulting in the stimulation of Smad target gene expression.

Animals↗
PubMed1991

Polyamines, vascular smooth muscle, and deoxycorticosterone acetate-salt hypertension.

This study was performed to determine if an alteration in vascular polyamine contents is associated with the development of deoxycorticosterone acetate-salt hypertension. The effects of chronic administration of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase and thus polyamine biosynthesis, on vascular polyamine contents, structure, and function as well as the development of hypertension was studied. Control and deoxycorticosterone acetate-salt rats received either tap water or a drinking solution containing alpha-difluoromethylornithine for 6 weeks, during which period systolic blood pressures were recorded. Vascular reactivity studies were performed on rings of aorta and tail artery. Medial thickness, vessel weight, and vascular polyamine contents were also assessed in these arteries. alpha-difluoromethylornithine treatment had no significant effect on either systolic blood pressure or vascular structure, function, and polyamine contents of control animals. The elevation in blood pressure and the increase in medial thickness, ring weight, and vascular polyamine contents as well as altered vascular reactivity observed in deoxycorticosterone acetate-salt rats was significantly attenuated by alpha-difluoromethylornithine treatment. These results are the first to demonstrate that vascular polyamine contents are elevated in the deoxycorticosterone acetate-salt rat and that chronic alpha-difluoromethylornithine treatment prevents the rise in vascular polyamines as well as the elevation in blood pressure and attendant changes in the vasculature. Thus, the increase in vascular polyamines may comprise a critical link between the initiating stimuli and the alterations in vascular structure and function implicated in the pathogenesis of deoxycorticosterone acetate-salt hypertension.

Acetylcholine↗
PubMed1995

In situ substrate specificity and ultrastructural localization of polyamine oxidase activity in unfixed rat tissues.

Data concerning the substrate specificity and the exact intracellular localization of the polyamine-catabolizing enzyme polyamine oxidase are conflicting. Biochemical studies have shown that N1-acetylation of spermine and spermidine dramatically increases the specificity of these compounds for peroxisomal polyamine oxidase to produce spermidine and putrescine, respectively. On the other hand, polyamine oxidase activity was demonstrated histochemically both in peroxisomes and in cytoplasm of several tissues, using spermidine and/or spermine as substrate. To elucidate the in situ substrate specificity of polyamine oxidase and the localization of its activity, enzyme activity was detected in rat liver, kidney, and duodenum at the light and electron microscopic levels. For this purpose, unfixed cryostat sections were applied to avoid changes in enzyme activity owing to chemical fixation. Spermine, spermidine, their N1-acetylated forms, and putrescine were used as substrates, and cerium ions as capturing agent for H2O2. Control reactions were performed in the absence of substrate or in the presence of substrate and specific oxidase inhibitors. At the light microscopic level, final reaction product specifically generated by polyamine oxidase activity was found exclusively in a granular form in hepatocytes, epithelial cells of proximal tubules of the kidney, and epithelial cells of duodenal villi with N1-acetylspermidine or N1-acetylspermine as substrates. Final reaction product was not observed in any of the tissues after incubation in the presence of putrescine, spermidine, or spermine. Formation of specific final reaction product was prevented by incubation in the presence of a specific polyamine oxidase inhibitor, but it was not affected by a diamine oxidase inhibitor. Ultrastructural studies revealed that polyamine oxidase activity is localized exclusively to the matrix of peroxisomes of kidney and liver and to microperoxisomes of the duodenum. The localization patterns obtained with unfixed tissues are in agreement with biochemical data. Strong intraperoxisomal, interperoxisomal, and intercellular heterogeneity in polyamine oxidase activity was found in all tissues investigated.

Animals↗
PubMed1991

Polyamines: from molecular biology to clinical applications.

The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects, yet despite several decades of intensive research work, their exact physiological function remains obscure. Chemically these compounds are organic aliphatic cations with two (putrescine), three (spermidine) or four (spermine) amino or amino groups that are fully protonated at physiological pH values. Early studies showed that the polyamines are closely connected to the proliferation of animal cells. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Out of these four enzyme, the two decarboxylases represent unique mammalian enzymes with an extremely short half life and dramatic inducibility in response to growth promoting stimuli. The regulation of ornithine decarboxylase, and to some extent also that of adenosylmethionine decarboxylase, is complex, showing features that do not always fit into the generally accepted rules of molecular biology. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur. The biosynthesis of the polyamines thus offers a meaningful target for the treatment of certain hyperproliferative diseases, most notably cancer. Although most experimental cancer models responds strikingly to treatment with polyamine antimetabolites--namely, inhibitors of various polyamine synthesizing enzymes--a real breakthrough in the treatment of human cancer has not yet occurred. It is, however, highly likely that the concept is viable. An especially interesting approach is the chemoprevention of cancer with polyamine antimetabolites, a process that appears to work in many experimental animal models. Meanwhile, the inhibition of polyamine accumulation has shown great promise in the treatment of human parasitic diseases, such as African trypanosomiasis.

Adenosylmethionine Decarboxylase↗
PubMed1996

Regulation of polyamine synthesis and transport by fibroblast growth factor in aortic smooth muscle cells.

Basic-FGF (FGF2) is implicated as a regulator of smooth muscle cell proliferation that develops after arterial injury. Polyamines are essential for cell growth and differentiation and may mediate some of the FGF2-elicited responses. To examine this possibility, the effect of FGF2 on polyamine synthesis and uptake was tested on rat arterial smooth muscle cells. Exposure of cells to FGF2 for 24 and 48 h resulted in increased intracellular polyamine content. Ornithine decarboxylase (ODC) activity increased in FGF2-treated cells after 6 h of treatment, whereas no increases were detected in ODC mRNA steady-state levels. Basic-FGF increased maximal polyamine transport rate without changes in Km. Treatment with actinomycin D decreased polyamine transport. The effect of cyclohexamide on polyamine uptake was dose dependent. These studies indicate that treatment of vascular smooth muscle cells with FGF2 results in increases in intracellular polyamine content, polyamine synthetic activity, and polyamine transport.

Animals↗
PubMed1997

Multiple polyamine regulatory pathways control compensatory cardiovascular hypertrophy in coarctation hypertension.

While a number of factors may initiate structural alterations within the cardiovascular system in response to hypertension, there are obligate cellular signaling mechanisms, such as the polyamines, through which they must operate. This study examined the effects of polyamine synthesis inhibition using eflornithine, a suicide inhibitor of ornithine decarboxylase on blood pressure, compensatory remodeling of the cardiovascular system, and cardiac and aortic polyamine contents using an aortic coarctation model in rats. Eflornithine treatment failed to reduce carotid arterial blood pressure and actually significantly elevated vascular pressure above and below the coarctation site by 14 days of hypertension. Eflornithine only transiently reduced aortic polyamine content of hypertensive rats while this agent reduced coarctation-induced aortic medial wall thickening and the synthesis/deposition of fibronectin and laminin in the hypertensive aorta. Increases in left ventricular mass and polyamine content were concomitantly reduced in hypertensive rats administered eflornithine. These results suggest that multiple polyamine regulatory pathways may maintain vascular polyamine content in response to aortic coarctation; however de novo polyamine synthesis is essential for select aspects of vascular remodeling, including matrix synthesis. Cardiac tissue, in contrast, may rely principally on de novo polyamine synthesis.

Animals↗