Antizyme inhibitor: a defective ornithine decarboxylase or a physiological regulator of polyamine biosynthesis and cellular proliferation

2007 ◽  
Vol 35 (2) ◽  
pp. 311-313 ◽  
Author(s):  
A. Keren-Paz ◽  
Z. Bercovich ◽  
C. Kahana
Keyword(s):  
Ornithine Decarboxylase ◽  
Cellular Proliferation ◽  
Cellular Transformation ◽  
Polyamine Biosynthesis ◽  
Polyamine Synthesis ◽  
Homologous Protein ◽  
Antizyme Inhibitor ◽  
Physiological Regulator ◽  
Growth Promoting

ODC (ornithine decarboxylase) is a central regulator of cellular polyamine synthesis. ODC is a highly regulated enzyme stimulated by a variety of growth-promoting stimuli. ODC overexpression leads to cellular transformation. Cellular ODC levels are determined at transcriptional and translational levels and by regulation of its degradation. Here we review the mechanism of ODC degradation with particular emphasis on AzI (antizyme inhibitor), an ODC homologous protein that appears as a central regulator of ODC stability, cellular polyamine homoeostasis and cellular proliferation.

Expression of protooncogenes c-fos and c-myc in healing of gastric mucosal stress ulcers

1994 ◽  
Vol 266 (5) ◽  
pp. G878-G886 ◽  
Author(s):  
J. Y. Wang ◽  
L. R. Johnson
Keyword(s):  
Gastric Mucosa ◽  
Ornithine Decarboxylase ◽  
Thymidine Incorporation ◽  
Healing Process ◽  
Mucosal Healing ◽  
Xiphoid Process ◽  
Stress Ulcers ◽  
Polyamine Biosynthesis ◽  
Polyamine Synthesis ◽  
Oxyntic Gland

The current study determines the hypothesis that expression of protooncogenes c-fos and c-myc is involved in the mechanism of polyamine-stimulated healing in gastric mucosal stress ulcers. Rats were fasted 22 h, placed in restraint cages, and immersed in water to the xiphoid process for 2-6 h. Animals were killed either immediately after stress or at 2-h intervals up to 24 h after 6 h of stress. Stress caused both visible lesions and induction of ornithine decarboxylase (ODC) activity in the oxyntic gland mucosa after 2 h. Increased ODC activity was paralleled by increases in the mucosal polyamines putrescine, spermidine, and spermine. Exposure to stress led to appearance of c-fos mRNA and oncoprotein in the gastric oxyntic gland mucosa at 2 h and its disappearance by 4 h. Baseline expression of c-myc was enhanced significantly after 6 h of stress and remained elevated for 4 h. This change in the expression of c-fos and c-myc mRNA and oncoprotein preceded an increased rate of [3H]thymidine incorporation into mucosal DNA. Administration of alpha-difluoromethylornithine (DFMO, 500 mg/kg ip) totally prevented the marked increases in ODC activity and polyamine levels. DFMO also completely inhibited the expression of c-fos and significantly decreased c-myc mRNA and oncoprotein in the gastric mucosa of stressed rats. The healing process, which was significant by 12 h, was markedly inhibited by DFMO. These results show that 1) mucosa exposed to stress exhibits increased expression of c-fos and c-myc following increased polyamine synthesis and 2) inhibition of polyamine biosynthesis by DFMO decreases both protooncogene expression and mucosal healing.

Intestinal ornithine decarboxylase: half-life and regulation by putrescine

1990 ◽  
Vol 258 (2) ◽  
pp. G308-G315 ◽  
Author(s):  
K. Iwami ◽  
J. Y. Wang ◽  
R. Jain ◽  
S. McCormack ◽  
L. R. Johnson
Keyword(s):  
Ornithine Decarboxylase ◽  
Intestinal Mucosa ◽  
Half Life ◽  
Time Course ◽  
Polyamine Synthesis ◽  
Mammalian Tissues ◽  
Growth Promoting ◽  
Mucosal Growth ◽  
Rate Limiting ◽  
Intestinal Crypt Cell

Ornithine decarboxylase (ODC) is the primary rate-limiting enzyme for polyamine synthesis. ODC levels are increased in most tissues, including the intestinal mucosa, by growth-promoting agents. This enzyme has a brief half-life of from 5 to 30 min in mammalian tissues and is regulated by its product; putrescine. The current study examines the turnover and regulation of ODC in the mucosa of the small intestine. With the use of scraped intestinal mucosa from cycloeximide-treated rats, the time course of the decline in ODC activity yielded a half-life of approximately 22 min. Labeling enzyme protein with [3H]difluoromethylornithine (DFMO) resulted in a nearly identical estimation of half-life. ODC activity of mucosa from isolated gut segments stimulated by luminal glycine (0.1-0.4 M) was enhanced 60-100% by 10 mM putrescine administered luminally. Putrescine alone had no effect on ODC. In contrast, 10(-7) M putrescine prevented 80% of the ODC activity stimulated by asparagine in IEC-6 cells (a rat intestinal crypt cell line). The half-life of ODC in unstimulated IEC-6 cells was 20 min and increased to 35 min in cells exposed to 10 mM asparagine. These data demonstrate that ODC of nonproliferating villous cells is regulated differently from the identical enzyme in proliferating crypt cells. Therefore, conclusions regarding mucosal growth should not be based totally on ODC activity from whole mucosa, since it is essentially a measure of only the enzyme present in the villous cells.

Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor

2009 ◽  
Vol 46 ◽  
pp. 47-62 ◽  
Author(s):  
Chaim Kahana
Keyword(s):  
Turnover Rate ◽  
Cellular Proliferation ◽  
Cellular Growth ◽  
26S Proteasome ◽  
Cellular Viability ◽  
Cellular Functions ◽  
Polyamine Biosynthesis ◽  
Cellular Processes ◽  
Antizyme Inhibitor ◽  
Key Enzyme

Polyamines are small aliphatic polycations present in all living cells. Polyamines are essential for cellular viability and are involved in regulating fundamental cellular processes, most notably cellular growth and proliferation. Being such central regulators of fundamental cellular functions, the intracellular polyamine concentration is tightly regulated at the levels of synthesis, uptake, excretion and catabolism. ODC (ornithine decarboxylase) is the first key enzyme in the polyamine biosynthesis pathway. ODC is characterized by an extremely rapid intracellular turnover rate, a trait that is central to the regulation of cellular polyamine homoeostasis. The degradation rate of ODC is regulated by its end-products, the polyamines, via a unique autoregulatory circuit. At the centre of this circuit is a small protein called Az (antizyme), whose synthesis is stimulated by polyamines. Az inactivates ODC and targets it to ubiquitin-independent degradation by the 26S proteasome. In addition, Az inhibits uptake of polyamines. Az itself is regulated by another ODC-related protein termed AzI (antizyme inhibitor). AzI is highly homologous with ODC, but it lacks ornithine-decarboxylating activity. Its ability to serve as a regulator is based on its high affinity to Az, which is greater than the affinity Az has to ODC. As a result, it interferes with the binding of Az to ODC, thus rescuing ODC from degradation and permitting uptake of polyamines.

scholarly journals Cloning of Antizyme Inhibitor, a Highly Homologous Protein to Ornithine Decarboxylase

1996 ◽  
Vol 271 (7) ◽  
pp. 3340-3342 ◽  
Author(s):  
Yasuko Murakami ◽  
Tamotsu Ichiba ◽  
Senya Matsufuji ◽  
Shin-ichi Hayashi
Keyword(s):  
Ornithine Decarboxylase ◽  
Homologous Protein ◽  
Antizyme Inhibitor

scholarly journals 3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

2005 ◽  
Vol 49 (7) ◽  
pp. 2857-2864 ◽  
Author(s):  
Robin Das Gupta ◽  
Tanja Krause-Ihle ◽  
Bärbel Bergmann ◽  
Ingrid B. Müller ◽  
Alex R. Khomutov ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Red Blood Cells ◽  
Ornithine Decarboxylase ◽  
Mechanism Of Action ◽  
Blood Cells ◽  
Polyamine Biosynthesis ◽  
Polyamine Synthesis ◽  
Promising Strategy

ABSTRACT The intraerythrocytic development of Plasmodium falciparum correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the S-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional P. falciparum ODC-AdoMetDC, with Ki values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 μM. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against P. falciparum independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in P. falciparum, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.

Secretin inhibits induction of ornithine decarboxylase activity by gastrin in duodenal mucosa and IEC-6 cells

1994 ◽  
Vol 267 (2) ◽  
pp. G276-G284 ◽  
Author(s):  
J. Y. Wang ◽  
S. A. McCormack ◽  
M. J. Viar ◽  
L. R. Johnson
Keyword(s):  
Ornithine Decarboxylase ◽  
Cellular Proliferation ◽  
Duodenal Mucosa ◽  
Significant Inhibition ◽  
Decarboxylase Activity ◽  
Mrna Levels ◽  
Polyamine Biosynthesis ◽  
Rate Limiting Step ◽  
Normal Rat ◽  
Epidermal Growth

Ornithine decarboxylase (ODC) catalyzes the first rate-limiting step in polyamine biosynthesis, and increased ODC activity is one of the earliest biochemical events associated with the induction of cellular proliferation. The current study examines the regulation of ODC activity in rat duodenal mucosa and IEC-6 cells (a line of normal rat intestinal crypt cells) in response to the trophic hormone, gastrin, and its inhibitor, secretin. Rats were fasted 22 h before the various treatments, and ODC activity was measured in scraped duodenal mucosa. Gastrin significantly increased ODC activity within 3 h to 4.3 times control levels. The effect of gastrin was totally inhibited by 5 micrograms/kg secretin. In doses of 5 or 10 micrograms/kg, secretin had no effect on basal ODC. Epidermal growth factor (EGF) and refeeding fasted rats also significantly increased ODC activity in duodenal mucosa, but the effects of EGF and refeeding were not prevented by secretin. In cultured IEC-6 cells, ODC activity was significantly increased after exposure to gastrin, 5% dialyzed fetal bovine serum (FBS), EGF, and asparagine. Secretin in doses ranging from 10(-10) to 10(-6) M caused a linear and significant inhibition of the stimulation of ODC activity by gastrin. No dose of secretin affected basal ODC activity or enzyme activity stimulated by 5% dialyzed FBS, EGF, or asparagine in IEC-6 cells. The ODC mRNA levels in IEC-6 cells were also increased after exposure to gastrin. Administration of secretin significantly prevented the stimulated expression of the ODC gene in cells treated with gastrin.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Cloning of antizyme inhibitor, a highly homologous protein to ornithine decarboxylase.

1996 ◽  
Vol 271 (16) ◽  
pp. 9870
Author(s):  
Yasuko Murakami ◽  
Tamotsu Ichiba ◽  
Senya Matsufuji ◽  
Shin-inchi Hayashi
Keyword(s):  
Ornithine Decarboxylase ◽  
Homologous Protein ◽  
Antizyme Inhibitor

scholarly journals Expression of ileal glucagon and peptide tyrosine-tyrosine genes. Response to inhibition of polyamine synthesis in the presence of massive small-bowel resection

1992 ◽  
Vol 286 (3) ◽  
pp. 737-741 ◽  
Author(s):  
R G Taylor ◽  
D J Beveridge ◽  
P J Fuller
Keyword(s):  
Small Bowel ◽  
Ornithine Decarboxylase ◽  
Bowel Resection ◽  
Intestinal Adaptation ◽  
Small Bowel Resection ◽  
Polyamine Biosynthesis ◽  
Polyamine Synthesis ◽  
Rate Limiting ◽  
Massive Small Bowel Resection ◽  
Sustained Increase

Massive small-bowel resection results in a marked adaptive response in the residual terminal ileum. Increased polyamine synthesis is a necessary component of this response. The ileal L-cell-derived peptides enteroglucagon and peptide tyrosine tyrosine (PYY) have been implicated as humoral mediators of this response. We have previously reported a rapid and sustained increase in glucagon mRNA concentrations after massive small-bowel resection. In this study using an inhibitor of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase, we have demonstrated that the response of the glucagon and PYY genes to massive small-bowel resection is dependent on polyamine biosynthesis. In addition, we have examined the response of both the ornithine decarboxylase and c-jun genes in this model of intestinal adaptation.

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