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

To elucidate the role of polyamine metabolism in the regulation of mesangial cell growth, we examined the involvement of ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis, in the mitogenesis of cultured rat mesangial cells (MCs). Resting MCs, stimulated with fetal calf serum (FCS 10%), showed an induction of ODC activity from undetectable values in resting cells to mean = 5035 nmol CO2/10(10) cells.hr (range 3157 to 7154, N = 5), which is 25-fold above the detection limit. We found a single peak of ODC activity eight to ten hours after stimulation, declining to 22 to 34% of peak levels after 24 hours. 3H-thymidine (TdR) uptake, an S-phase marker of MC replication, peaked at 24 hours, reaching 10.7-fold values of resting MCs. ODC mRNA levels were low in resting cells. After serum stimulation there was a two- to 10-fold increase in ODC mRNA with a maximum after six hours. ODC activity with similar kinetics but lower peak levels was also induced by incubating MCs with mitogens, such as platelet-derived growth factor (PDGF-AB 20 ng/ml), arginine vasopressin (AVP 10(-7) M), phorbol myristate acetate (PMA 10(-7) M), interleukin 1 alpha and beta (IL-1 alpha 10 U/ml, IL-1 beta 10 U/ml). In the presence of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, the growth rate of MCs, assessed by cell counts and by 3H-TdR uptake, was markedly reduced by 62 to 100%. This antiproliferative effect of DFMO could be reversed by addition of putrescine, the reaction product of ODC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of ornithine decarboxylase for proliferation of mesangial cells in culture. 174 18

The G0/G1 to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be specifically blocked by the administration of interferon (IFN) to the system. In the present communication, we studied whether IFN inhibits the early events in the G0/G1 phase that are initiated by the platelet-derived growth factor (PDGF). The results show that IFN inhibits most of the PDGF-mediated increase of c-myc, ornithine decarboxylase, and beta-actin mRNAs measured 3 hr after stimulation. c-fos mRNA levels are reduced by IFN as early as 20 min after exposure of the quiescent cells to PDGF. The expression of several genes that belong to the competence gene family is, therefore, inhibited by IFN and this could account for the failure of the IFN-treated cells to enter into the S phase when growth factors present in the platelet-poor plasma are added. We also report that the PDGF-mediated increase in the uptake of deoxyglucose is not impaired by IFN, thus suggesting that the early effects of IFN on gene expression do not result from inhibition of binding of PDGF to its cell-surface receptors. Unlike the direct stimulatory effect of PDGF, which is not sensitive to cycloheximide, the inhibitory effect of IFN on c-myc mRNA levels depends in part on protein synthesis. We propose that a putative product of one of the IFN-induced genes could mediate the decrease in expression of the PDGF-regulated gene family.
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PMID:Inhibitory effects of interferon on the expression of genes regulated by platelet-derived growth factor. 241 66

IGF-I stimulated the mitogenesis of Nb2 cells in the presence of suboptimal mitogenic concentrations of prolactin (PRL, 0.01 or 0.1 ng/ml). In the presence of 1 ng/ml or 10 ng/ml, concentrations of PRL that produced a maximal or near maximal mitogenic response in Nb2 cells, the addition of insulin-like growth factor-I (IGF-I) at 5 or 10 ng/ml did not further enhance mitogenesis. This effect was selective for IGF-I since IGF-II, epidermal growth factor (EGF), insulin, transforming growth factor-beta (TGF-beta) or platelet-derived growth factor (PDGF) did not stimulate mitogenesis in the presence or absence of PRL. That the ability of IGF-I to stimulate mitogenesis of these cells required PRL was suggested by the ability of PRL antiserum to block the IGF-I effect. Monoclonal antibody to IGF-I reduced the mitogenic response to one identical to PRL alone. In the presence of a suboptimal mitogenic concentration of PRL, IGF-I was an equally effective comitogen when added at 0 time or at 6 h after PRL stimulation, suggestive of an effect of IGF-I in late G1 phase of the cell cycle. Effects of IGF-I on ornithine decarboxylase, a G1 enzymatic marker, were compatible with this interpretation. In order to be assured that IGF-I exerted its action through a receptor-mediated process, we evaluated the presence of IGF-I receptors on Nb2 cells. Receptors were present which bound IGF-I greater than IGF-II much greater than insulin. The IC50 was 35 nM for IGF-I, 280 nM for IGF-II and 875 nM for insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhancement of prolactin (PRL)-stimulated mitogenesis of Nb2 rat lymphoma cell cultures by insulin-like growth factor I (IGF-I). 277 31

We have established the patterns of ornithine decarboxylase activity (an enzyme related to cell growth, differentiation, and proliferation) during rat testicular development and studied the effect of epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-type beta (TGF-beta), and a serum-free, hormone/growth factor-supplemented medium (TKM) on ornithine decarboxylase (ODC) activity in Sertoli-spermatogenic cell cocultures and cultured seminiferous peritubular cells prepared from sexually immature rats (20-22 days old). Results were correlated with timing of ODC activities during rat testicular development. We have found that: (1) although EGF, alone or combined with PDGF and TGF-beta, and TKM stimulated ODC activity in Sertoli-spermatogenic cell cocultures after 6 and 24 h of stimulation, PDGF exerted an inhibitory effect, and (2) cultured peritubular cells stimulated with EGF, PDGF, TGF-beta (and their combinations), and TKM displayed an increase in ODC activity after 6 h of stimulation, but ODC activities for most of these treatments declined considerably 24 h after stimulation. Light microscopic autoradiographic studies of [3H]thymidine labeled samples demonstrated that (1) clones of spermatogenic cells traverse S phase synchronously, (2) Sertoli cells are not significantly radiolabeled, probably because of contact inhibition achieved by high cell plating density, and (3) peritubular cells are significantly [3H]thymidine labeled in the presence of TKM, a culture medium that facilitates spermatogenic cell long-term viability and differentiation. We conclude that TKM and EGF have stimulatory effects on the biochemical pathway that precedes synchronous DNA synthesis in spermatogonia and preleptotene spermatocytes, and that ODC activity is a sensitive marker for monitoring these events.
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PMID:Ornithine decarboxylase activity during rat spermatogenesis in vivo and in vitro: selective effect of hormones and growth factors. 289 Jun 48

The activation of protein kinase C and protein phosphorylation by tumor promoters were examined using quiescent cultures of BALB/3T3 and C3H/10T1/2 cells, because in these cells tumor promoters enhance chemically induced transformation and also induce DNA synthesis and ornithine decarboxylase. The cytosol and membrane fractions were partially purified, and the activity of protein kinase C was assayed. In quiescent cells, protein kinase C activity was found only in the cytosol fraction. Treatment with 100 ng of 12-O-tetradecanoylphorbol-13-acetate or teleocidin B per ml caused rapid translocation of protein kinase C from the cytosol to the membrane fraction. The activity in the cytosol disappeared almost completely after 15 min when the activity in the membrane reached a peak. The membrane activity gradually decreased to the control level after 6 h, while no activity reappeared in the cytosol within 6 h. Under these circumstances, a membrane protein with a molecular weight of 90,000 and pl of 4.0-4.4 (termed p90) was specifically phosphorylated, possibly by the activated protein kinase C, in both cell-free and intact-cell systems. On treatment of quiescent BALB/3T3 cells with 100 ng of 12-O-tetradecanoylphorbol-13-acetate, p90 phosphorylation increased 2-fold in 1 min, reaching a peak in 15 min of 3.4-fold the initial value. The phosphorylation of p90 increased with increase in the concentrations of 12-O-tetradecanoylphorbol-13-acetate between 0.1 and 10 ng/ml and reached a plateau at 10 ng/ml. p90 phosphorylation also occurred on exposure of the cells to non-phorbol ester tumor promoters (mezerein and teleocidin B) and growth factors, such as platelet-derived growth factor and fibroblast growth factor. p90 was not immunoprecipitated by antibody against the insulin receptor. Phosphorylation of p90 occurred at a serine residue. The present study suggests that activation of protein kinase C and phosphorylation of p90 by it are early events leading to tumor promotion.
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PMID:Activation of protein kinase C and specific phosphorylation of a Mr 90,000 membrane protein of promotable BALB/3T3 and C3H/10T1/2 cells by tumor promoters. 308 Feb 29

Cultivated arterial smooth muscle cells were used to study the effects of platelet-derived growth factor (PDGF) on polyamine synthesis and of polyamine synthesis inhibitors on initiation of DNA synthesis by PDGF. Quiescent (serum-starved) cells showed no detectable activity of ornithine decarboxylase (ODC), the first and overall rate-limiting enzyme in polyamine synthesis, and had low levels of the polyamines putrescine, spermidine and spermine. PDGF caused a marked increase in ODC activity, with a peak after 6 h followed by a rapid decline. The rise in enzyme activity was blocked by actinomycin D and cycloheximide, suggesting control at the transcriptional and translational levels, alpha-Difluoromethylornithine (DFMO), a catalytic and irreversible inhibitor of ODC, prevented the appearance of enzyme activity. The cellular content of putrescine increased distinctly in response to PDGF, with a peak after 8 h, abolished by simultaneous treatment with DFMO. In contrast, the concentrations of spermidine and spermine changed but little within the 20-h period examined here. DFMO inhibited the initiation of DNA synthesis without affecting the length of the prereplicative lag phase and was fully active if added within 4 h after PDGF. The effect of DFMO on DNA synthesis was counteracted by addition of polyamines to the culture medium and exogenous polyamines were also found to stimulate DNA synthesis in PDGF-free medium (spermine greater than spermidine greater than putrescine). It is concluded that induction of ODC and putrescine synthesis are integral parts in the mitogenic response of arterial smooth muscle cells to PDGF.
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PMID:Induction of ornithine decarboxylase activity and putrescine synthesis in arterial smooth muscle cells stimulated with platelet-derived growth factor. 310 75

Ornithine decarboxylase activity was assessed in serum-deprived quiescent NIH-3T3 murine fibroblasts after exposure to a variety of growth-promoting factors. Ornithine decarboxylase activity increased after treatment with phorbol 12-myristate 13-acetate (PMA), fetal calf serum, bovine pituitary fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and the synthetic diacyglycerol sn-1,2-dioctanolyglycerol but not after treatment with epidermal growth factor, insulin, 4 alpha-phorbol 12,13-didecanoate, sn-1,2-dibutyrylglycerol, or the calcium ionophore A23187. Activity peaked at 3-4 h and returned to basal levels after 8 h. To determine the importance of protein kinase C in this increase, cells were pretreated with PMA for 16 h to make the cells effectively deficient in protein kinase C; this deficiency was documented by direct measurement of enzyme activity and immunoreactivity. The ornithine decarboxylase response to each mitogen was then compared in cells pretreated with PMA or control conditions. PMA pretreatment abolished the increase in ornithine decarboxylase activity due to additional PMA and decreased but did not eliminate the ability of serum, FGF, and PDGF to cause increases in ornithine decarboxylase activity. Similarly, pretreatment with PMA abolished the ability of additional PMA to increase ornithine decarboxylase mRNA levels but did not prevent the increases in these mRNA levels caused by FGF or serum. These data suggest that the increases in ornithine decarboxylase activity and mRNA levels that occur in quiescent fibroblasts in response to serum, FGF, or PDGF are due to activation of at least two separate pathways, one involving protein kinase C and the other independent of protein kinase C.
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PMID:Effects of mitogens on ornithine decarboxylase activity and messenger RNA levels in normal and protein kinase C-deficient NIH-3T3 fibroblasts. 373 13

Nerve growth factor (NGF) promotes neuronal differentiation of PC12 pheochromocytoma cells. We show here that within 5 min after its addition, NGF transiently stimulates c-fos proto-oncogene and actin transcription by greater than 100-fold in nonsynchronized PC12 cells. c-myc and ornithine decarboxylase transcription are also transiently activated, but more slowly. The corresponding mRNAs are induced as well. Two weeks' exposure to NGF causes no significant changes in the transcription of these and a variety of other genes analyzed; however, c-fos mRNA levels are increased severalfold under these conditions. Neuronally differentiated PC12 cells retain the capacity for rapid transcriptional responses. Removal of NGF from such cells for several hours followed by its readdition results in rapid induction of c-fos and actin transcription. These NGF-promoted transcriptional changes in PC12 cells are similar to those previously observed in quiescent fibroblasts stimulated by platelet-derived growth factor (Greenberg, M.E., and Ziff, E.B. (1984) Nature 311, 433-438). This rapid transcriptional activation in PC12 cells could be necessary for neuronal differentiation, but is apparently not sufficient since diverse agents without differentiating activity such as epidermal growth factor, insulin, dibutyryl cAMP, phorbol ester, and elevated K+ were also found to induce transcription. These results suggest that c-fos, c-myc, and actin induction may be general nuclear responses to growth or differentiation factors in a variety of different cell types.
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PMID:Nerve growth factor and epidermal growth factor induce rapid transient changes in proto-oncogene transcription in PC12 cells. 387 54

The polypeptide growth factors, nerve growth factor, epidermal growth factor, and platelet-derived growth factor, as well as insulin do not induce ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) unless a minimal concentration of an ornithine decarboxylase-inducing amino acid, such as asparagine, is present in the medium. The effects of the growth factors were studied in appropriately responsive cell lines: pheochromocytoma (PC12) cells for nerve and epidermal growth factors, fibroblasts (NIH 3T3) for platelet-derived growth factor, and fibroblasts and hepatoma (KRC-7) cells for insulin. The nonmetabolizable amino acid analog alpha-aminoisobutyric acid can replace asparagine, indicating that the covalent modification of the inducing amino acid is not necessary for the induction of ornithine decarboxylase by these growth factors. For the same intracellular concentration of the inducing amino acid, the presence of the growth factors induces higher levels of ornithine decarboxylase. The evidence indicates that these growth factors do not induce ornithine decarboxylase by raising the intracellular concentration of amino acids but rather act synergistically with the inducing amino acid. Evidence is provided that the induction of polyamine-dependent growth by these growth factors is mediated by amino acids. The relationship of these results to the A and N amino acid transport systems and to the Na+ influxes in relation to growth is discussed.
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PMID:Induction of ornithine decarboxylase activity by insulin and growth factors is mediated by amino acids. 389 32

Human diploid fibroblast cells lose replicative potential after a certain number of population doublings. We use this experimental system to investigate the role of oxidative damage in cellular aging. Treating cells with H2O2 at < 300 microM did not affect the viability of the majority of cells when judged by morphology, trypan blue exclusion, and protein synthesis. However, the treatment caused a dose-dependent inhibition of DNA synthesis. After a 2-hr treatment with 200 microM H2O2, the cells failed to respond to a stimulus of serum, platelet-derived growth factor, basic fibroblast growth factor, or epidermal growth factor by synthesizing DNA, and the loss of response could not be recovered by 4 days. Subcultivation showed that, as in senescent cells, division of the treated cells was inhibited. The life-time cumulative growth curve showed that the loss of replication due to H2O2 treatment was cumulative and irreversible. The H2O2 treatment decreased the number of the population doublings in the rest of the life span by 35.3 +/- 10.3%. Enzymatic assays indicated that, like the cells in their senescent state, the treated cells were less able to activate ornithine decarboxylase and thymidine kinase. Furthermore, subcultivation after the H2O2 treatment showed that the cells developed the morphology of senescent cells. In conclusion, sublethal treatment of H2O2 "stunned" F65 cells and caused the cells to enter a state resembling senescence.
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PMID:Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. 818 82


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