Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.17 (ornithine decarboxylase)
 6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were carried out to determine whether the actions of prolactin on the metabolism of the mammary gland may involve polyamines. In mouse mammary gland explants that were preincubated for 2 days with insulin plus hydrocortisone, the rate of [3H]leucine incorporation into casein was enhanced in a prolactin-like manner during a further incubation with spermidine plus cyclic GMP or phospholipase A. Putrescine (0.5 mM) plus PGF2alpha, cyclic GMP or arachidonic acid also enhanced the rate of casein synthesis: but PGF2alpha plus 0.5 mM arginine, ornithine or spermine had no effect. Methyl GAG, an inhibitor of the enzyme S-adenosyl-L-methionine decarboxylase (which is required for the conversion of putrescine to spermidine), abolished the putrescine plus PGF2alpha stimulation of casein synthesis. Since this drug did not affect the action of spermidine plus PGF2alpha on casein synthesis, the specific action of spermidine on casein synthesis is suggested. Neither arginine, ornithine nor the polyamines, by themselves, affected the rate of [3H]uridine incorporation into RNA or the rate of [3H]leucine incorporation into casein. Spermidine levels were elevated within 4 h after adding prolactin to explants which were preincubated for 2 days with insulin plus hydrocortisone; this effect was apparent during incubation periods of up to 48 h with prolactin. Arginase and ornithine decarboxylase activities were also elevated in response to prolactin. Arginase activity was only elevated, however, during long incubation periods with prolactin, i.e., during incubation periods of longer than 2 days. In contrast, ornithine decarboxylase activity was elevated by prolactin within a 30 min incubation period; this effect was maximal after 2 h and persisted during exposure periods of up to 24 h.
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PMID:Regulation of casein synthesis by polyamines in mammary gland explants of mice. 18 30

Thyrotropin (TSH) stimulation of ornithine decarboxylase (ODC) activity and polyamine levels was studied in vitro in rat thyroids. The elevation in ODC activity was related to the concentration of TSH in the incubation medium with peak activity at a concentration of 25mU/ml. ODC activity with 50 mU/ml of TSH was 3 to 5-fold higher than control activity at 5 h of incubation; this stimulation was enhanced by the addition of 0.5 mM 3-isobutyl-l-methyl xanthine (MIX), a phosphodiesterase inhibitor. Dibutyryl cyclic AMP (DbcAMP) also stimulated ODC activity with a dose response up to 2.0 mm. The increase in ODC activity with TSH and MIX was prevented by incubation with actinomycin D (10 microgram/ml) or puromycin (0.2 mM). Putrescine concentrations in rat thyroids rose to three times basal levels after 6 h of incubation with TSH and MIX; no significant elevation in spermidine or spermine was observed after up to 7 h incubation. The increase in tissue putrescine preceded a rise in [3H]uridine incorporation into acid-soluble material that occurred at 7 h. The results suggest that stimulation of thyroid ODC activity by TSH is mediated by a cyclic AMP; the data further are consistent with a role for polyamines in the control of RNA synthesis in the thyroid.
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PMID:In vitro stimulation of thyroid ornithine decarboxylase activity and polyamines by thyrotropin. 19 94

1. The activation of human peripheral blood lymphocytes by phytohaemagglutinin in vitro was accompanied by striking increases in the concentrations of the natural polyamines putrescine, spermidine and spermine. 2. The enhanced accumulation of polyamines could be almost totally abolished by dl-alpha-difluoromethylornithine, a newly discovered irreversible inhibitor of l-ornithine decarboxylase (EC 4.1.1.17), or by methylglyoxal bis(guanylhydrazone) {1,1'-[(methylethanediylidene)dinitrilo]diguanidine}, an inhibitor of S-adenosyl-l-methionine decarboxylase (EC 4.1.1.50). The inhibition of polyamine accumulation was associated with a marked suppression of DNA synthesis, which was partially or totally reversed by low concentrations of exogenous putrescine, spermidine, spermine and cadaverine and by higher concentrations of 1,3-diaminopropane. 3. In contrast with some earlier studies, we found that methylglyoxal bis(guanylhydrazone), at concentrations that were sufficient to prevent polyamine accumulation, also caused a clear inhibition of protein synthesis in the activated lymphocytes. Similar results were obtained with difluoromethylornithine. The decrease in protein synthesis caused by both compounds preceded the impairment of DNA synthesis. The inhibition of protein synthesis by difluoromethylornithine was fully reversed by exogenous putrescine, spermidine and spermine, and that caused by methylglyoxal bis(guanylhydrazone) by spermidine and spermine. In further support of the idea that the inhibition of protein synthesis by these compounds was related to the polyamine depletion, we found that difluoromethylornithine caused a dose-dependent decrease in the incorporation of [(14)C]leucine into lymphocyte proteins which closely correlated with the decreased concentrations of cellular spermidine. 4. Difluoromethylornithine and methylglyoxal bis(guanylhydrazone) also elicited a variable depression in the incorporation of [(3)H]uridine and [(14)C]adenine into total RNA. The apparent turnover of lymphocyte RNA remained essentially unchanged in spite of severe polyamine depletion brought about by difluoromethylornithine. 5. The present results, as well as confirming the anti-proliferative action of the inhibitors of polyamine biosynthesis, suggest that polyamine depletion may interfere with reactions at different levels of gene expression.
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PMID:Suppression of the formation of polyamines and macromolecules by DL-alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) in phytohaemagglutinin-activated human lymphocytes. 43 70

The in vitro incorporation into mouse placenta of [14C]leucine, [3H]uridine, and [3H]thymidine fell between gestational days 14 and 19 by 61, 30 and 72%, respectively; ornithine decarboxylase activity fell by 75%. Injection of dexamethasone resulted on day 14 in values normally found between days 15 and 18. These changes coincided with rising activity in fetal liver of the enzyme 11 beta-hydroxysteroid:NADP oxidoreductase, which reduced the abundant 11-dehydrocorticosterone to the active hormone, corticosterone. These events appear to be part of a spectrum of effects produced by corticosteroids on fetal growth at this time, probably mediated primarily by fetal liver.
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PMID:Corticosteroids, ornithine decarboxylase activity and the incorporation of leucine, uridine, and thymidine into mouse placenta. 74 71

1. An injection of D-galactosamine (GalN) into mice together with a lipopolysaccharide (LPS or endotoxin), interleukin-1 (IL-1) or tumour necrosis factor (TNF), sensitized the mice and induced fulminant hepatitis with severe congestion resulting in rapid death. Since LPS and these cytokines induce ornithine decarboxylase (ODC) and histidine decarboxylase (HDC) in the liver and spleen of mice, the effects of GalN on the induction of ODC and HDC in these organs were examined. 2. The induction of ODC by LPS, IL-1 or TNF was suppressed by GalN in the liver, and this suppression preceded the hepatic congestion. There was good agreement between the degree of hepatic congestion and the suppression of ODC induction by various amounts of GalN. The induction of ODC in the spleen was suppressed only at the highest dose of GalN examined. 3. GalN is known to deplete uridine 5'-triphosphate (UTP), resulting in the suppression of RNA and protein synthesis. An injection of uridine, the precursor of UTP, diminished the GalN-induced suppression of ODC induction by LPS and prevented the hepatic congestion and death. 4. LPS-pretreatment before injection of LPS plus GalN prevented the suppression of ODC activity and prevented the hepatic congestion and death. 5. An injection of putrescine, the product of ODC, prolonged survival time and delayed the development of hepatic congestion. However, injection of an ODC inhibitor into the mice given LPS did not produce hepatic congestion. 6. The induction of HDC in the liver by LPS, IL-1 or TNF was not suppressed by GalN and, at high doses, the response to LPS was enhanced. An inhibitor of HDC neither prevented the hepatic congestion nor enhanced the protective effect of putrescine.7. Although GalN in combination with IL-la induced a markedly higher HDC activity than was observed when it was combined with TNFa, and suppressed the induction of ODC, the former combination at the doses used did not produce hepatic congestion or death. However, the sensitization to TNFa by GalN was markedly potentiated by IL-la.8. These results suggest that suppression of the induction of ODC by GalN may be one cause of the sensitization to LPS, IL-1 or TNF, and that the induction of HDC, i.e. histamine formation, may not be involved in this sensitization.9. These results are consistent with the hypothesis that both IL-1 and TNF are involved in the sensitization to LPS.
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PMID:Ornithine and histidine decarboxylase activities in mice sensitized to endotoxin, interleukin-1 or tumour necrosis factor by D-galactosamine. 147 81

The effects of 5-fluorouracil (FUra) treatment on thymidine kinase (TKase) activity were examined in vivo in CD8F1 mice bearing first generation CD8F1 mouse mammary tumors. TKase activity was not affected by low dose FUra25 (25 mg/kg), a dose which substantially inhibited thymidylate synthase (TSase), but was severely inhibited 24 hr following treatment with FUra100, a weekly maximally tolerated dose, as judged by activity measurements and labeling of DNA with [3H]thymidine. The amount of (FU)RNA was increased markedly with increasing FUra dose from 0.4 nmol/mg DNA at FUra25 to 2.2 nmol/mg DNA at FUra100. At FUra100, TKase activity gradually declined over 24 hr to less than 10% of the control value, remained low for a further 48 hr, and then was gradually restored to control levels by 168 hr. The loss of TKase activity followed the incorporation of FUra into RNA which peaked at 4-5 hr. TKase activity was not restored by removal of endogenous inhibitors but was restored by treatment with uridine. TKase activity was not inhibited by therapeutic levels of methotrexate (300 mg/kg). TKase from murine colon 38 carcinoma was also severely inhibited, but the activity from colon 26 was only partially (50%) inhibited. Ornithine decarboxylase was also inhibited by FUra100 treatment in the CD8F1 tumor. These results demonstrate that certain short-lived, proliferation-related enzymes are affected by FUra doses higher than those required for TSase inhibition, and this effect appears to correlate with incorporation of FUra into RNA. Thus, in some tumors high doses of FUra can inhibit salvage as well as de novo synthesis of thymidylate providing an increased block of DNA synthesis and increased therapeutic advantage.
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PMID:Loss of murine tumor thymidine kinase activity in vivo following 5-fluorouracil (FUra) treatment by incorporation of FUra into RNA. 172 9

Recently gonadotropin releasing hormone (GnRH) and its agonistic analogs were demonstrated to have some direct actions in accessory reproductive organs. In our study the effects of GnRH and its analogs on some steroid hormone induced responses were investigated. GnRH and its analogs inhibited estradiol induced ornithine decarboxylase (ODC) and glucosamine-6-phosphate synthase activities in the uterus of rat. These enzymes which are markers for cell proliferation are regulatory enzymes in the biosynthetic pathways of polyamines and glycoproteins, respectively. Similarly, GnRH and its analogs also inhibited testosterone stimulated ODC activity in ventral prostate of rat. In addition, GnRH analog inhibited incorporation of radioactive precursors into RNA and protein induced by estradiol in uterus or dihydrotestosterone (DHT) in ventral prostate. In an effort to elucidate the mechanism of action of GnRH in uterus, it was found that GnRH analog treatment does not alter the estradiol receptor content in vivo. Also, GnRH does not show any effect on radioactive estradiol binding to its receptor in vitro. Hence, the inhibitory actions of GnRH in uterus may not involve estradiol receptors. However, GnRH analogs were found to have post-transcriptional effects. It was observed that DHT induced poly(A) polymerase activity in ventral prostate and estradiol induced poly(A) polymerase activity in uterus were inhibited by GnRH analog treatment. It was further observed that GnRH inhibited incorporation of [3H]uridine into poly(A)+ RNA of ventral prostate. This indicates that the inhibitory effects of GnRH involve post-transcriptional mechanisms.
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PMID:Direct inhibitory actions of GnRH on accessory reproductive organs of rat. 241 40

In the early chick embryo, inhibition of polyamine synthesis by alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, blocks development at gastrulation. This effect was paralleled by a marked suppression of RNA and protein synthesis. There was no major change in cell cycle distribution in DFMO-treated embryos. Nevertheless, analysis of DNA synthesis and mitotic index indicated a prolongation of the cell cycle, possibly affecting all the phases. The inhibition of RNA synthesis in polyamine-depleted embryos, as evaluated by [3H]uridine incorporation, was not a result of reduced uptake or expansion of the UTP pool, and there was no deficiency or major imbalance among the ATP, GTP, and CTP pools. On the basis of agarose gel electrophoretic analyses of the various RNA species, and experiments using RNA synthesis inhibitors with different modes of action (actinomycin D, alpha-amanitin, and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole), it was concluded that the DFMO-induced gastrular arrest was due to general inhibition of transcription.
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PMID:Transcriptional inhibition in early chick embryos as a result of polyamine depletion. 242 48

The thymic leukemia cell line EL4 has been shown to produce the lymphokine Interleukin-2 (IL-2) following stimulation with phorbol ester (PMA). We investigated intracellular enzyme pathways triggered by phorbol stimulation using an EL4 cell line which responds to PMA with IL-2 synthesis (EL4r) and one which does not produce IL-2 following stimulation (EL4nr). By comparing these two cell lines we hoped to establish which enzyme activities were associated with IL-2 synthesis. The enzyme pathways studied included calcium/phospholipid dependent protein kinase (C-kinase) activity, the induction of polyamine synthesis, RNA, DNA and protein synthesis and finally IL-2 production. Our results indicate that both EL4 cell lines have a receptor for PMA, which can activate the C-kinase enzyme. Further, in both cell lines PMA activates the nuclear synthesis of polyamines as demonstrated by ornithine decarboxylase induction. Both RNA and protein synthesis measured by 3H-uridine and 3H-leucine uptake respectively appear comparable between EL4r and EL4nr. The only difference in cellular responsiveness between EL4r and EL4nr was in the 3H-thymidine uptake, and IL-2 production. IL-2 production or lack of production was established by 3H-uridine and 3H-thymidine incorporation as well as viable cell count using the IL-2 dependent cell line CTLL-2. We, therefore, conclude that EL4r and EL4nr cells show similar intracellular responses to phorbol ester except for 3H-thymidine uptake and detectable IL-2 production. Our results suggest that failure of PMA-stimulated EL4nr cells to produce IL-2 is either due to inability of this cell line to synthesize IL-2 or the production of defective IL-2. It is not due to failure of PMA to activate C-kinase or the subsequent nuclear events.
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PMID:The activation of calcium/phospholipid dependent protein kinase and the association with interleukin-2 production. 242 45

Gossypol, a drug which has been shown to be an inhibitor of kinase C activity in mouse mammary tissues, is shown to abolish several of the actions of prolactin in cultured mouse mammary gland explants. The prolactin effects that are abolished include its stimulatory effects on ornithine decarboxylase activity, the rate of [3H]uridine incorporation into RNA, the rate of [3H]leucine incorporation into a casein-rich phosphoprotein fraction, and the rate of [14C]acetate incorporation into lipids. Since the inhibitory concentrations of gossypol employed in these studies correspond well with the gossypol concentrations required to inhibit kinase C activity, we conclude that ongoing kinase C activity is essential for prolactin to express its differentiative actions in mammary tissues.
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PMID:Effect of kinase C inhibitor, gossypol, on the actions of prolactin in cultured mouse mammary tissues. 243 40


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