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)

c-Myc is an oncogenic transcription factor involved in the regulation of cell proliferation, differentiation and apoptosis. The direct targets of c-Myc mediating these various processes are slowly being unravelled. This study indicates that the ornithine decarboxylase (ODC) gene is a physiological transcriptional target of c-Myc in association with induction of cell proliferation and transformation, but not with induction of apoptosis. In addition to the two conserved CACGTG c-Myc-binding sites in the first intron, the CATGTG motif in the 5'-flanking region of the murine odc is also shown to be a functional c-Myc response element. odc is thus a c-Myc target with three binding sites a distance apart. Transient transfection studies with different c-Myc, Max and Mad constructs in COS-7 cells showed that the balance between c-Myc/Max, Max/Max and Max/Mad complexes is crucial for the regulation, resulting in either transactivation or transrepression of an ODC-CAT reporter gene. Transcription of both ODC-CAT and endogenous odc was strongly induced in HeLa cells expressing tetracycline-regulated c-Myc, concomitant with c-Myc promoting the S-phase entry of the cells. Transformation of NIH3T3 cells by c-Ha-ras-(Val12) oncogene was reversed by expression of transcriptionally inactive c-Myc, which was associated with repression of ODC-CAT expression. Further, the c-Myc-induced transactivation of ODC-CAT in COS-7 cells was suppressed by co-expression of the retinoblastoma tumor suppresser pRb, evidently as a result of pRb directly or indirectly interacting with c-Myc. Importantly, the endogenous c-Myc and pRb proteins were also found to associate in Colo 320HSR cells under physiological conditions. These results suggest that c-Myc and pRb can interact in vivo, and may in part control some aspects of cell proliferation and transformation through modulation of odc expression.
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PMID:Transcriptional regulation of the ornithine decarboxylase gene by c-Myc/Max/Mad network and retinoblastoma protein interacting with c-Myc. 1256 11

The objective of the current study was to investigate the effect of resveratrol, a naturally occurring polyphenol with cancer chemopreventive properties, on polyamine metabolism in the human colonic adenocarcinoma cell line Caco-2. We demonstrated that inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was due to attenuated ODC protein and mRNA levels (50-200 microM). The naturally occurring resveratrol analog piceatannol (100 microM) also diminished ODC activity, protein and mRNA levels, whereas the green tea polyphenol (-)-epigallocatechin gallate (EGCG; 100 microM) exerted only weak effects on ODC. The transcription factor c-Myc, a positive regulator of the odc gene was attenuated by resveratrol treatment and to a lesser extent by piceatannol and EGCG. S-Adenosylmethionine decarboxylase, an enzyme that synthesizes higher polyamines, was concomitantly inhibited by resveratrol and piceatannol treatment, whereas EGCG did not affect its activity. In addition resveratrol, piceatannol and EGCG enhanced spermidine/spermine N(1)-acetyltransferase activity, an enzyme that degrades polyamines in cooperation with polyamine oxidase. Intracellular levels of spermine and spermidine were not affected, whereas putrescine and N(8)-acetylspermidine concentrations increased after incubation with resveratrol. These events were paralleled by an increase of the activator protein-1 constituents c-Fos and c-Jun. Whereas DNA-binding activity of c-Jun remained unchanged, DNA-binding activity of c-Fos was significantly enhanced by resveratrol and piceatannol, but inhibited by EGCG. The data suggest that growth arrest by resveratrol is accompanied by inhibition of polyamine synthesis and increased polyamine catabolism. C-Fos seems to play a role in this context. Effects of piceatannol on polyamine synthesis were similar, but not as potent as those exerted by resveratrol.
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PMID:Resveratrol-induced modification of polyamine metabolism is accompanied by induction of c-Fos. 1266 6

Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the beta-subunit mutated (c4) lacking hypoxia-inducible factor-1 (HIF-1) activity, were differentially susceptible to apoptosis by hepatocyte growth factor (HGF). The c4 cells were 40% apoptotic 48 h after HGF treatment. On the contrary, the wild-type c1c7 cells showed modest signs of apoptosis only at 72 h. The revertant vT[2] cells, consisting of c4 cells stably transfected with HIF-1beta expression vector, behaved as the parental cells. To understand the mechanisms of this different sensitivity, we examined a panel of genes involved in apoptosis: ornithine decarboxylase, c-Myc and p53 protein levels progressively decreased while JNK1, caspase 8 and 3 activities persistently increased in c4 cells undergoing apoptosis. Distinct time-related events in c1c7 cells were the transient activations of JNK1 and caspase 8 followed by the accumulation of ODC and c-Myc proteins. The proapoptotic effect of HGF in c4 hepatocarcinoma cells seems to be related to HIF-1 deficiency with loss of cytoprotective and signalling functions. This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation, which in turn causes BID cleavage and cytochrome c release. The effector caspase 3 is also activated.
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PMID:Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency. 1282 40

Cell cycle machinery controls not only cell growth but also cell survival and death. For example, overexpression of c-Myc or E2F1, which are involved in G1/S transition, causes apoptosis under certain conditions. Furthermore, endogenous E2F1 also participates in apoptosis, as evidenced by the defect of apoptosis in E2F1-deficient mice. Candidate molecules that mediate c-Myc- and E2F1-enhanced apoptosis include p14/p19ARF, ornithine decarboxylase and lactate dehydrogenase-A (for c-Myc) as well as p14/p19ARF, p73, Apaf-1 and caspase-3 (for E2F1). c-Myc also activates the CD95/Fas-FADD-mediated death signal. c-Myc and E2F1 inhibit NF-kappaB activities induced by TNFalpha or reactive oxygen species. Therefore, c-Myc and E2F1 regulate cell growth and death not only by inducing transcription but also by modulating signal transduction pathways.
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PMID:E2F1 and c-Myc in cell growth and death. 1285 85

Hexachlorobenzene (HCB) is a lipophilic chemical compound that is widely distributed in the environment. HCB is known to cause liver tumors in experimental animals. In the present study the in vivo effect of HCB treatment on ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) activities, free polyamine content, and c-Myc, c-Fos, and c-Jun protein levels in rat liver were investigated. HCB (1000 mg/kg body weight) increased hepatic immunodetectable c-Myc, c-Fos, and c-Jun levels after 6 h, and ODC activity and spermine and putrescine content after 18 and 24 h, while maximum stimulation of PTK activity occurred at 12 h. PTK and ODC activities varied in a dose-dependent manner. The time-course of c-Myc, c-Fos, and c-Jun protein levels was different for each proto-oncogene. They were all elevated at the second day of treatment, while only c-Fos and c-Jun remained elevated after 10 days of HCB exposure. These data jointly suggest that the increase in ODC activity may be the consequence of proto-oncogene induction. The alterations in PTK activity suggest that the growth factor signal transduction pathway may be involved in the regulation of the proto-oncogene levels or/and ODC activity. The decrease in PTK activity after the first day, even in the presence of alpha-D-Difluoromethylornithine (DFMO), an inhibitor of ODC activity, suggests that it is not regulated by polyamines. These results may be relevant to the early molecular events involved in HCB tumor promoter activity in rat liver.
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PMID:Hexachlorobenzene-induced early changes in ornithine decarboxylase and protein tyrosine kinase activities, polyamines and c-Myc, c-Fos and c-Jun proto-oncogenes in rat liver. 1460 Feb 89

Time-dependent changes in polyamine metabolism and c-Myc expression are reported in kidney of mice treated with cisplatin, a widely used anticancer drug. We show that cisplatin significantly induces the expression of two enzymes critical to proper homeostasis of cellular polyamines, ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT). We also document the cross-talk between signalling pathway(s) induced by cisplatin injury to renal tubules and the testosterone/androgen receptor pathway. Their interaction results in a decrease in testosterone-induced ODC activity and ODC mRNA level, and in differential modulation of SSAT expression. Moreover, cisplatin and antifolate CB 3717, another nephrotoxic drug examined, severalfold up-regulate expression of c-Myc mRNA, albeit with different kinetics. However, cisplatin, contrary to CB 3717, does not induce renal hepatocyte growth factor (HGF)/c-Met expression being without effect on HGF mRNA level and significantly down-regulating c-Met transmembrane receptor message. In conclusion, these in vivo studies document significant cisplatin-induced modulation of polyamine biosynthesis/degradation and up-regulation of c-Myc expression, and suggest that c-Myc transcription factor is involved in the induction of ODC in kidney injured with antifolate, but not with cisplatin.
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PMID:Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression. 1527 53

Helicobacter pylori infection causes chronic inflammation of the gastric mucosa that results from an ineffective immune response. We have demonstrated that one underlying mechanism is induction of macrophage apoptosis mediated by polyamines. The transcription factor c-Myc has been linked to induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. We determined whether H. pylori stimulates transcriptional activation of ODC in macrophages, whether this occurs via c-Myc, and whether these events regulate activation of apoptosis. H. pylori induced a significant increase in ODC promoter activity that peaked at 6 h after stimulation and was closely paralleled by similar increases in ODC mRNA, protein, and enzyme activity. By 2 h after stimulation, c-Myc mRNA and protein expression was induced, protein was translocated to the nucleus, and there was specific binding of a consensus probe for c-Myc to nuclear extracts. Both an antennapedia-linked inhibitor of c-Myc binding (Int-H1-S6A,F8A) and transfection of a c-Myc dominant-negative construct significantly attenuated H. pylori-induced ODC promoter activity, mRNA, enzyme activity, and apoptosis in parallel. Transfection of ODC small interfering RNA inhibited ODC activity and apoptosis to the same degree as inhibition of c-Myc binding. These studies indicate that c-Myc is an important mediator of macrophage activation and may contribute to the mucosal inflammatory response to pathogens such as H. pylori by its effect on ODC.
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PMID:Helicobacter pylori-induced macrophage apoptosis requires activation of ornithine decarboxylase by c-Myc. 1584 84

Topoisomerase II inhibitors are widely used in cancer chemotherapy. However, their use is limited by severe adverse effects to normal tissues, including cardiotoxicity. One approach to reduce the cytotoxicity in normal tissues may be to sensitize cancer cells to the toxicity of these agents, allowing them to be administered in a lower and safer dose. A hallmark of many types of cancer is overexpression of c-Myc, and a molecule which targets c-Myc will affect the cancer cells more significantly than the normal tissues. This report demonstrates that pretreatment of cells with a polypeptide, which inhibits c-Myc transcriptional function causes cells to be more susceptible to the topoisomerase II inhibitors doxorubicin and etoposide. Inhibition of c-Myc and Max dimerization by this polypeptide leads to as much as a 2-fold reduction in the doxorubicin and etoposide IC(50) in three different cell lines tested. Furthermore, the c-Myc inhibitor affects the cell cycle distribution of MCF-7 breast cancer cells by enhancing the G(0)/G(1) accumulation induced by doxorubicin and etoposide. We have shown that this effect is not due to enhanced drug accumulation or inhibited drug efflux. Rather, it is likely due to the transcriptional consequences of c-Myc inhibition, specifically reduction in the levels of the polyamine synthesizing enzyme ornithine decarboxylase. In summary, our results suggest that polypeptides, which inhibit c-Myc transcriptional function, may prove to be a useful tool in combination therapy with topoisomerase II inhibiting drugs.
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PMID:Enhancing the antiproliferative effect of topoisomerase II inhibitors using a polypeptide inhibitor of c-Myc. 1631 34

HIF-1, a hypoxia inducible transcription factor, plays a pivotal role in the cellular response to hypoxia by activating genes involved in glucose metabolism, vascular remodeling, and erythropoiesis. We identified Mxi1, a c-Myc antagonist, as a novel target gene induced in hypoxia. Mxi1 was not induced in cells deficient in ARNT (HIF-1beta), suggesting that Mxi1 is a transcriptional target of the HIF-1 complex. Notably, c-Myc protein levels decreased during hypoxia but were stabilized by a proteasome inhibitor. Analysis of downstream transcriptional targets of c-Myc during hypoxia revealed that genes regulated by c-Myc, such as ornithine decarboxylase (ODC), were downregulated during hypoxia. In contrast, genes that are regulated by c-Myc and HIF-1, such as LDH-A, were upregulated. Mxi1 protects against c-Myc-dependent sensitization to hypoxia-induced apoptosis. The results suggest a coordinated mechanism for opposing c-Myc signaling during hypoxia that is mediated by a reduction in c-Myc levels, the induction of Mxi1, and a dominant effect of HIF-1 transcriptional activity.
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PMID:Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. 1631 23

Somatic cells in the majority of colorectal polyps and cancers contain mutations/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is involved in normal intestinal development and acts to influence a variety of cellular processes. Loss of APC function leads to intestinal neoplasia in both mice and humans. APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator. Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers. Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, is under clinical evaluation as a colorectal cancer chemopreventive agent. APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.
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PMID:A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene. 1638 48


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