Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Known stimulators of the calcium-sensitive phospholipid-dependent protein kinase C were investigated for their ability to regulate ornithine decarboxylase (ODC) activity in rat kidney. In the control state ODC activity averaged 84.9 +/- 13.2 pmol mg-1 min-1 in a soluble fraction (n = 4). Four hours following the intraperitoneal injection of 2.5 nmol/g body weight of phorbol 12-myristate 13-acetate (PMA) activity increased to 284.1 +/- 10.9 pmol mg-1 min-1 (n = 4; p less than 0.001). A chemically distinct stimulator of PKC, mezerein, had a similar effect on ODC in kidney and liver. Activity stimulated by PMA in kidney was dependent on the synthesis of both new mRNA and protein. Four hours following unilateral nephrectomy (UNX), ODC activity increased from 112.9 +/- 15.6 pmol mg-1 min-1 in sham-operated animals to 319.1 +/- 30.0 pmol mg-1 min-1 in animals postnephrectomy (n = 4; p less than 0.01). Activity of ODC stimulated by phorbol esters was not additive to that seen following UNX. Twelve hours following the induction of renal growth by folic acid. ODC-specific activity was at basal levels. Neither UNX nor PMA were able to stimulate ODC at this time. These data suggest that protein kinase C may be involved in the regulation of ODC in rat kidney.
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PMID:Regulation of ornithine decarboxylase in rat kidney. 239 94

The activation of protein kinase C, induction of ornithine decarboxylase (ODC), and hyperplasia have been suggested to be linked, sequential processes resulting from phorbol ester application to mouse skin. However, evidence is presented indicating that these events are not necessarily linked or dependent on one another and that significant differences exist in these responses between phorbol ester promotion sensitive (SSIN) and resistant (C57BL/6J) mice. The epidermis from SSIN mice treated with a single application of 12-O-tetradecanoylphorbol-13-acetate (TPA) displayed a large induction of ODC and a subsequent extensive hyperplasia. A second TPA treatment at 24 or 48 h after the first did not result in ODC induction (refractory state), and protein kinase C was shown to be down-regulated at these times. By 72 h, however, a responsive state had returned even through protein kinase C remained down-regulated. The epidermis of C57BL/6J responds to a single application of TPA with a level of ODC induction similar to that of the SSIN mice. Protein kinase C was down-regulated by approximately 75% after 24 h and was virtually completely down-regulated at 48 and 72 h (95-97%). In contrast to the above findings for the sensitive mice, however, little, if any, hyperplasia was produced. In addition, while a second TPA treatment at 24 h did not result in ODC induction (refractory state), hyperplasia did occur within 24 to 48 h. When the second TPA application was given 48 h after the first, at a time when protein kinase C was down-regulated, an overinduction of ODC occurred, as well as subsequent hyperplasia. Furthermore, a significant number of papillomas resulted when these increased treatment frequencies, i.e., once a day or every other day, were used to promote dimethylbenz(a)anthracene-initiated C57BL/6J mice. It is concluded that, while hyperplasia remains an apparent requirement for tumor promotion, the ODC induction following an initial TPA treatment is insufficient for or not causally related to this hyperplasia. In addition, subsequent ODC induction, at least in the C57BL/6J mouse, is probably not mediated by protein kinase C.
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PMID:Correlation of phorbol ester promotion in the resistant C57BL/6J mouse with sustained hyperplasia but not ornithine decarboxylase or protein kinase C. 281 17

The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with calcium ionophores has been shown to bypass the requisite antigen- or lectin-induced signal for lymphocyte mitogenesis. This suggests that protein kinase C activation and calcium mobilization may be early events required for lymphocyte proliferation. Therefore, the relationship(s) of protein kinase C activation and calcium mobilization to ornithine decarboxylase induction and cellular proliferation were examined in a rat node lymphoma cell line (Nb2) which is dependent upon prolactin (PRL) for mitogenesis. TPA enhanced PRL-stimulated Nb2 node lymphoma cell ornithine decarboxylase induction and [3H]thymidine incorporation. Addition of a calcium ionophore (A23187) to cultures containing TPA plus PRL increased ornithine decarboxylase above PRL alone or PRL plus TPA but inhibited proliferation compared to the PRL plus TPA regimen. Exposure of cells to TPA or TPA plus A23187 increased [3H]thymidine incorporation in a similar manner to that demonstrated for low-dose PRL. However, optimal concentrations were only 20-25% as effective as mitogens as was optimal PRL. Protein kinase C and calmodulin antagonists inhibited PRL-stimulated ornithine decarboxylase induction and proliferation. Ca2+ chelation or cation channel antagonism inhibited both PRL-stimulated responses. The cyclic AMP analogue, 8Br-cAMP, inhibited PRL-stimulated ornithine decarboxylase activity as well as cellular proliferation processes assessed by [3H]thymidine incorporation. Finally, tumor-promoting phorbol esters inhibited 125I-rPRL binding. These data strongly suggest that protein kinase C activation and calcium mobilization are requisite events for PRL-stimulated ornithine decarboxylase induction and cellular proliferation in Nb2 node lymphoma cells. An additional component that is linked to alterations in K+ channeling is also implicated. These data support a role for protein kinase C in PRL-coupled mitogenesis. However, other critical Ca2+ and/or ion-induced events are also required.
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PMID:Prolactin stimulation of ornithine decarboxylase and mitogenesis in Nb2 node lymphoma cells: the role of protein kinase C and calcium mobilization. 309 4

Insulin and tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) share some biological activities in normal hepatocytes and in some lines of cultured hepatoma cells. To investigate the possibility that some of these common effects might involve a common pathway, we examined the effects of insulin and PMA on several biological processes in normal and protein kinase C-deficient H4IIE rat hepatoma cells. Protein kinase C deficiency was achieved by preincubating the cells in high concentrations of PMA, and was documented by direct enzyme measurement in soluble and particulate cellular fractions, and by analysis of immunoreactive protein kinase C concentrations in whole cellular homogenates. In the protein kinase C-deficient cells, the following actions of insulin remained at near normal levels: stimulated phosphorylation of the ribosomal protein S6; activation of a ribosomal S6 protein kinase; and increases in ornithine decarboxylase activity and mRNA accumulation. PMA stimulated all of these responses in the normal cells, but none of them in the PMA-pretreated cells. We conclude that insulin can exert some of its actions in a normal manner in protein kinase C-deficient H4IIE hepatoma cells (ATCC CRL 1548) and that some of the actions insulin holds in common with PMA may be due to common activation of one or more distal pathways. A candidate for such a distal step is activation of the ribosomal protein S6 protein kinase.
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PMID:Insulin action in normal and protein kinase C-deficient rat hepatoma cells. Effects on protein phosphorylation, protein kinase activities, and ornithine decarboxylase activities and messenger ribonucleic acid levels. 333 10

When a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was performed 12 h before the second application, ornithine decarboxylase (ODC) induction by the second application of TPA was markedly suppressed (refractory state). However, at intervals of 96 h between the first and the second application, the ODC activity induced by the second application of TPA was higher (enhanced state) than the activity induced by the single application. When various anti-tumor promoting agents, i.e. p-bromophenacyl bromide, nordihydroguaiaretic acid, quercetin, 1-tosylamide-2-phenylethyl chloromethyl ketone, retinoic acid and palmitoylcarnitine, were applied concurrently with the first TPA application, the ODC induction in the refractory state was restored only by palmitoylcarnitine, but not by other antitumor promoting agents. None of these anti-tumor promoting agents affected the ODC induction in the enhanced state. Stearoylcarnitine also had the restorative effect but was less effective than palmitoylcarnitine. Acetylcarnitine and palmitic acid were not effective. Pretreatment of mice with TPA 12 h or 96 h before the second TPA application resulted in the reduction or the increase in the Vmax values of ODC both for ornithine and pyridoxal-5'-phosphate, respectively. Palmitoylcarnitine restored these reduced Vmax values to the control values. Twelve hours after TPA treatment, the epidermal protein kinase C activity of both cytosol and particulate fractions decreased moderately. At 96 h after TPA application, protein kinase C activities of both cytosol and particulate fractions were fully or at least partially restored to the control levels. Protein kinase C activities both in the cytosol and the particulate fractions tended to be restored by palmitoylcarnitine, but the effect was not always reproducible. The TPA-induced refractory state and the enhanced state for ODC induction appear to result from the changes in the protein kinase C activities caused by TPA. However, it is not known whether such changes in the protein kinase C activities are the major causes for the TPA-induced refractory and/or enhanced state for ODC induction and whether or not the restorative effect of palmitoylcarnitine is due to its modulating action on protein kinase C activity.
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PMID:Palmitoylcarnitine reverses 12-O-tetradecanoylphorbol-13-acetate-induced refractory state for the TPA-caused ornithine decarboxylase induction in mouse epidermis. 333 15

We have analyzed the molecular mechanisms involved in ornithine decarboxylase (ODC) induction by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in T24 cells, an easily manipulable human epithelial cell line. The addition of as low as 10(-9)M TPA to T24 cells, cultured in a serum-free medium, resulted in ODC induction, with peak ODC activity occurring at about 6 h after TPA treatment. The induction of ODC activity correlates with the steady-state levels of ODC mRNA increased by TPA in T24 cells. TPA treatment did not elicit any change in the size (2.1 kb) of ODC mRNA as determined by Northern blot analysis by hybridization to nick-translated 32P-labeled cDNA prepared from either mouse or human ODC mRNA. Using the DNA-excess filter hybridization technique, we found that increased steady-state levels of ODC mRNA after TPA treatment may be the result of enhanced accumulation of newly synthesized ODC mRNA. The magnitude of the induction of ODC activity was proportional to the amount of ODC mRNA synthesis caused by TPA. In a pulse-chase experiment, we failed to detect any difference in the half-life of ODC mRNA in T24 cells after treatment with either TPA or the vehicle ethanol; the half-life of ODC mRNA was about 6 h in both cases. Furthermore, as determined by the "nuclear runoff transcription assay," the rate of transcription of ODC-gene was increased by treatment of T24 cells with TPA. These results provide direct evidence of the role of transcription-initiation in ODC-gene expression. The examination of the role of protein kinase C in ODC-gene transcription revealed that TPA or diacylglycerol did not induce the synthesis of ODC mRNA in PKC-deficient T24 cells. Taken together these results indicate that the TPA-increased synthesis of steady-state levels of ODC mRNA in T24 cells may be mediated by protein kinase C and is regulated at the transcriptional level.
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PMID:Involvement of protein kinase C in the transcriptional regulation of ornithine decarboxylase gene expression by 12-O-tetradecanoylphorbol-13-acetate in T24 human bladder carcinoma cells. 335 71

It has been reported that CD-1 and SENCAR mice are susceptible and C57BL/6 mice are resistant to skin tumor promotion caused by phorbol esters. Specific binding of a phorbol ester to its epidermal receptor site, epidermal protein kinase C activity, and ornithine decarboxylase (ODC) induction in epidermis were compared between tumor promotion-susceptible and -resistant strains of mice. Specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to the particulate fraction of the epidermis of C57BL/6 mice gave a similar dissociation constant (Kd) and a maximal number of binding sites (Bmax) to those of CD-1 mice. Protein kinase C activity of the epidermal 105,000 xg supernatant was not significantly different between C57BL/6 and CD-1 mice. Protein kinase C activity of the 105,000 xg pellet, however, was significantly higher in C57BL/6 mice than in CD-1 mice. A topical application of TPA to the skin caused epidermal ODC induction in all of these strains of mice. At any doses of TPA, TPA-induced epidermal ODC activity of C57BL/6 mice was always higher than those of SENCAR and CD-1 mice. Maximal induction of epidermal ODC by TPA was also highest in C57BL/6 mice among these three strains of mice. These results indicate that the mechanism of the difference in susceptibility of C57BL/6, CD-1 and SENCAR mice to the tumor-promoting action TPA resides in a step distal to or other than the protein kinase C activation and ODC induction.
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PMID:Comparison of some biochemical properties of epidermis in tumor promotion-susceptible and -resistant strains of mice. 341 20

To further understand the molecular mechanisms of bile acid-mediated colon tumor promotion, we have examined the possible role of protein kinase C (PKC) in this process. Protein kinase C has been implicated in tumor promotion because it is the receptor for the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA) and mediates the action of this compound as well as that of other tumor promoters and growth factors. Our studies show that, in a manner analogous to 12-0-tetradecanoyl-phorbol-13-acetate, deoxycholic acid (DOA) can induce a time-dependent cellular redistribution of PKC as well as a concentration-dependent overexpression of the ornithine decarboxylase gene. These results taken together with our previous findings demonstrating decreased levels of PKC in human colon carcinomas compared with adjacent normal mucosa provide evidence that PKC has a role in colon carcinogenesis.
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PMID:Studies on protein kinase C and colon carcinogenesis. 368 24

Caffeic acid phenethyl ester (CAPE) was evaluated for its potential in regulating keratinocyte proliferation. CAPE inhibited the proliferation of SV40 transformed keratinocytes (Z114) in a concentration- and time-dependent manner. Inhibition by CAPE was seen with 0.5 to 5.0 micrograms/ml at 48 h. Cell toxicity was observed at 10 micrograms/ml by changes in morphology and decreased viability. Pretreatment of Z114 cells with CAPE significantly prevented the full induction of ornithine decarboxylase (ODC) by epidermal growth factor (EGF) in a concentration- and time-dependent manner. Inhibition was observed with a concentration of CAPE as low as 1 microgram/ml, and complete inhibition of ODC induction by EGF occurred at 5 micrograms/ml. Northern analysis showed that treatment of cells with CAPE for 24 h suppressed EGF induction of ODC gene expression. Incubation of Z114 cells with CAPE for 24 h resulted in a concentration-dependent decrease in EGF binding and a 30% reduction in the EGF induced autophosphorylation of the EGF receptor. CAPE decreased both membranous and cytosolic PKC activity in a concentration- and time-dependent manner. Because significant inhibition of keratinocyte proliferation occurred at concentrations of CAPE that interfered with PKC activity and EGF signal transduction but did not cause overt toxicity, CAPE may prove useful for the treatment of hyperproliferative skin diseases.
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PMID:Caffeic acid phenethyl ester inhibits proliferation of human keratinocytes and interferes with the EGF regulation of ornithine decarboxylase. 883 88

Several studies have suggested that murine and human keratinocytes respond differently to phorbol 12-myristate 13-acetate (PMA). Using an in vitro assay, we found that in contrast to its effect on murine skin, PMA did not induce ornithine decarboxylase (ODC) activity in human skin biopsies. To explore the signalling induced by PMA and to determine whether an in vitro culture system could be used to predict biological activity of retinoids in human keratinocytes, we studied a simian virus 40 (SV40)-transformed human keratinocyte cell line. Epidermal growth factor (EGF) stimulates ODC activity and increases the steady-state level of ODC mRNA in a dose- and time-dependent manner in these cells [Prystowsky, Clevenger and Zheng (1993) Exp. Dermatol. 2, 125-132]. In this report, 10(-10) M-10(-7) M PMA induced ODC mRNA and enzyme synthesis at 7 h, but did not significantly induce ODC activity and inhibited the EGF induction of ODC activity. To explore the mechanism whereby PMA interfered with EGF signalling, the effect of PMA on EGF binding to its cell-surface receptor was studied; acute treatment with PMA (within 7 h) decreased EGF binding to 41-57% of the baseline level. In contrast, chronic treatment with PMA (24 h) increased EGF binding to 156% of the baseline level and was associated with an increase in quantity of EGF receptor protein. Protein kinase C (PKC) activation correlated with the acute decrease in EGF binding following PMA treatment. In summary, PMA induced ODC mRNA and ODC enzyme synthesis, while steady-state levels of immunoprecipitable ODC enzyme protein and ODC activity were not increased, demonstrating possible increased turnover of ODC enzyme protein. Additionally, PMA inhibited the induction of ODC by EGF through decreased EGF binding, possibly mediated by PKC activation. Finally treatment of the keratinocytes with retinoids including etretinate, Ro13-7410, etarotene, Ro40-8757, 13-cisretinoic acid, and acitretin blocked the PMA induction of ODC mRNA, suggesting this in vitro model could be a valuable screening assay for predicting biological activity in humans.
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PMID:Phorbol 12-myristate 13-acetate inhibits epidermal growth factor signalling in human keratinocytes, leading to decreased ornithine decarboxylase activity. 891 6


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