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)

Nuclear oncoproteins are among the most rapidly degraded intracellular proteins. Previous work has implicated the ubiquitin-mediated proteolytic system in the turnover of short-lived intracellular proteins. In the present study, we have evaluated the potential role of the ubiquitin system in the degradation of the specific nuclear oncoproteins encoded by the N-myc, c-myc, c-fos, p53 and E1A genes. Each of these nuclear oncoproteins was synthesized in vitro by transcription of the appropriate cDNA and translation of the resulting mRNA in the presence of [35S]methionine. Degradation of labeled proteins was monitored in the ubiquitin cell-free system. ATP stimulated the degradation of all the proteins between 3- and 10-fold. The degradation was completely inhibited by neutralizing antibody directed against the ubiquitin-activating enzyme, E1, the first enzyme in the ubiquitin-mediated proteolytic cascade. Moreover, degradation in E1-depleted lysates could be restored in each case by the addition of affinity-purified E1. These data suggest that the ubiquitin system mediates the degradation of these oncoproteins in vitro. Degradation of other proteins, such as superoxide dismutase, cytochrome c, enolase, RNase A, and ornithine decarboxylase, is not mediated by the ubiquitin cell-free system. This suggests that the nuclear oncoproteins studied here possess specific signals that target them for rapid turnover by this proteolytic pathway. Furthermore, the relative sensitivity to degradation of various E1A mutants in vivo is also maintained in the cell-free system, suggesting that the ubiquitin pathway may play a role in the cellular degradation of these proteins as well.
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PMID:Degradation of nuclear oncoproteins by the ubiquitin system in vitro. 184 34

We have constructed a recombinant retrovirus containing the murine c-myc and the neo gene and introduced the virus into the interleukin-3 (IL3) dependent myeloid cell line FDC-P1. Unregulated expression of the introduced c-myc gene is associated with both an increased viability and constitutive ornithine decarboxylase mRNA levels in FDC-P1 cells grown in the absence of IL3. FDC-P1 cells infected with the c-myc virus gave rise to IL3 independent lines. Three out of four independent lines have an activated endogenous c-myc or N-myc gene. We have also shown that c-myc mRNA levels are tightly regulated by IL3 in FDC-P1 cells. Taken together these results indicate that myc plays a critical role in the signal transduction pathway of IL3. Furthermore, activation of the N-myc gene may be one mechanism for myeloid cells to progress to complete IL3 independence.
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PMID:Role of myc in the abrogation of IL3 dependence of myeloid FDC-P1 cells. 245 16

The development of chemically induced hepatocellular carcinoma in the rat proceeds through a series of premalignant changes that may ultimately progress to a primary malignant tumor. Using the selection technique based on diminished binding of preneoplastic hepatocytes to tissue culture plates precoated with asialofetuin, we have isolated poly(A+)RNA from early preneoplastic foci as well as preneoplastic persistent nodules and primary hepatocellular carcinoma induced by the Solt-Farber protocol in the Fischer rat. The steady-state poly(A+)RNA levels of genes traditionally associated with growth, differentiation and/or transformation were then determined to address the question of their temporal expression in the multistep nature of cancer development. Ornithine decarboxylase- and P53-specific transcripts did not significantly change in preneoplastic foci but were increased in later-stage preneoplastic nodules and hepatocellular carcinoma. Albumin-specific transcripts were decreased in all hepatocellular carcinoma but there was no consistent coordinated increase in alpha-fetoprotein-specific transcripts. c-myc and raf transcripts increased at the very early preneoplastic foci stage and continued to increase throughout the neoplastic process. No L-myc or N-myc transcripts could be detected in any RNA sample. c-Ha-ras-specific transcripts were essentially unaltered in all RNA samples whereas no c-Ki-ras or N-ras transcripts could be detected throughout the neoplastic process. In addition, no dominant-acting transforming mutations in the ras gene family were detected by DNA transfection experiments using NIH/3T3 cells.
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PMID:Poly(A+)RNA levels of growth-, differentiation- and transformation-associated genes in the progressive development of hepatocellular carcinoma in the rat. 246 94

The genes for the M2 subunit of ribonucleotide reductase (RRM2), ornithine decarboxylase (ODC1), and 55,000-Daltons protein (P5), are amplified in hydroxyurea-resistant hamster and human cell lines. These genomic sequences have been mapped to hamster chromosome 7 and to human chromosome 2p24-25 near the cytogenetic location of the N-myc gene. We now report that genomic sequences homologous to N-myc are amplified in hydroxyurea-resistant hamster lung cell line, 600H, and the N-myc gene segregates with hamster chromosome 7 in mouse-hamster somatic cell hybrids. The conserved linkage group consisting of the RRM2, ODC1, P5, and N-myc in the hamster and human genomes prompted our investigation of human neuroblastomas. We report here that genomic DNA from 1 of 6 primary neuroblastoma tumors containing amplified N-myc also contains amplified sequences homologous to a hamster ODC cDNA.
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PMID:Amplification of N-myc and ornithine decarboxylase genes in human neuroblastoma and hydroxyurea-resistant hamster cell lines. 278 50

The effects of oncogene expression on phenomena related to polyamine metabolism were examined in Rat-1 cells stably transfected with EJ2-ras or N-myc oncogenes. In ras-transfected cells, ornithine decarboxylase activity was about 12-times higher than in either the parent or N-myc-transfected cell lines. By contrast, polyamine uptake was markedly increased in N-myc-transfected cells, as indicated by their enhanced sensitivity to the antiproliferative and enzyme regulatory effects of the polyamine analog, N1, N12-bis(ethyl)spermine (BESm), their intracellular accumulation of BESm and by their increased sensitivity to the growth inhibitory effects of methylglyoxalbis(guanylhydrazone)--another analog which utilizes the polyamine transport mechanism. These associations between N-myc and ras expression and critical aspects of polyamine metabolism suggest a possible role for the latter in facilitating the growth promoting properties of these oncogenes.
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PMID:Modulation of polyamine biosynthesis and transport by oncogene transfection. 314 63

alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC), was used to select two very highly drug-resistant cell lines, designated K562-DFMOr and V79-DFMOr. Both DFMO-resistant cell lines exhibited elevated ODC expression due to gene amplification. Moreover, the K562-DFMOr cells, but not the V79-DFMOr cells, had an elevated level of ribonucleotide reductase subunit R2 (R2) mRNA and an increased R2 gene copy number. By analysis of their electron paramagnetic resonance spectra, an increased level of the R2 protein was observed in the K562-DFMOr cells as compared to the wild type K562 cells. This is the first description of a DFMO-induced mutant cell line exhibiting coamplification of the genes for ODC and R2, and overexpression of their products. There was no coamplification of the N-myc protooncogene, which is located close to the ODC and R2 genes on human chromosome 2. The alterations exhibited by the K562-DFMOr cell line were shown to be stable for many passages and to convey resistance not only to DFMO but also to hydroxyurea, an inhibitor of ribonucleotide reductase and thus DNA replication. In the absence of the selective pressure exerted by DFMO, the V79-DFMOr cell line produced revertants by loss of ODC gene amplification within three passages. Coamplification of linked genes may turn out to be an important mechanism in the development of cross-resistance and should be considered when designing therapeutic strategies.
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PMID:Development of resistance to hydroxyurea during treatment of human myelogenous leukemia K562 cells with alpha-difluoromethylornithine as a result of coamplification of genes for ornithine decarboxylase and ribonucleotide reductase R2 subunit. 822 60

Although N-myc amplification is strongly associated with a poor prognosis, not all patients with neuroblastomas having N-myc amplification fare badly. To investigate whether genes other than N-myc are responsible for contributing to the prognosis, we examined seven cell lines and 87 primary tumours for co-amplification of candidate genes known to be present near the normal N-myc locus: ornithine decarboxylase (ODC), ribonucleotide reductase (RRM2), syndecan-1 and a DEAD box protein gene, DDX1. Sequence analysis of the pG21 cDNA clone previously reported to represent an expressed gene frequently co-amplified with N-myc, showed this to be from the DDX1 gene. No co-amplification with the first three genes was found in any of the cell lines or tumour samples. DDX1, however was found to be amplified along with N-myc in 4/6 (67%) cell lines and 6/16 (38%) of the N-myc amplified tumours. Co-amplification of DDX1 and N-myc was found more frequently in stage 4 or 4S tumours than lower stage (1-3) tumours. With the exclusion of a single 4S case, there was a highly significant reduction in the mean disease-free interval from 24.4 +/- 4.7 (SE, n = 10) months for cases with co-amplification of N-myc and DDX1 compared with 9.2 +/- 1.8 (SE, n = 5) months for those cases showing amplification of N-myc alone (P = 0.0056, Welch's unpaired t-test). No amplification of DDX1, ODC, RRM2, or syndecan-1 was found in the absence of N-myc amplification. These observation indicate that the N-myc amplicon is of varied size and/or position relative to the N-myc gene, with DDX1 representing at least one other gene frequently co-amplified with N-myc. Further studies are required to confirm the biological and prognostic significance of DDX1 co-amplification and to elucidate the role that DDX1 plays in tumour genesis and progression.
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PMID:Investigation of co-amplification of the candidate genes ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box gene, DDX1, with N-myc in neuroblastoma. United Kingdom Children's Cancer Study Group. 862 76

To elucidate the contribution of the N-Myc protein to neuroblastomas we have used a synthetic inducible expression system on the basis of the tetracycline repressor of E coli to reversibly express N-myc in a human neuroblastoma cell line in which expression of endogenous N-myc is barely detectable. Like the c-Myc protein, N-Myc up-regulates the expression of both alpha-prothymosin and ornithine decarboxylase. Induction of N-myc increases both the rate of DNA-synthesis and the proliferation rate, and shortens the G1 phase of the cell cycle. A comparison of cell populations in which the presence of N-Myc protein was restricted to different parts of G(zero)/G1 revealed that N-Myc is rate-limiting for cell cycle progression during the first 5 h after serum stimulation of quiescent cells providing direct evidence that Myc-proteins act early after mitogenic stimulation of quiescent cells.
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PMID:Conditional expression of N-myc in human neuroblastoma cells increases expression of alpha-prothymosin and ornithine decarboxylase and accelerates progression into S-phase early after mitogenic stimulation of quiescent cells. 876 2

The myc proto-oncogenes are transcription factors that directly regulate the expression of other genes, by binding to the specific DNA sequence, CACGTG. Among the target genes for c-Myc regulation are ECA39, p53, ornithine decarboxylase (ODC), alpha-prothymosin and Cdc25A. In this study we examined the involvement of c-Myc target genes in human oncogenesis induced by c-myc or N-myc. In MCF-7 breast cancer cells, the induction of c-myc expression by estrogen was followed by the induction of all the Myc targets that we examined, indicating that those genes can serve as c-Myc targets in human oncogenesis. Moreover, in breast tumors exhibiting c-myc overexpression, several Myc targets were also overexpressed. A clear correlation between the expression of c-myc and its targets was also detected in Burkitt's lymphomas, which involve a specific translocation of c-myc gene, but not in other lymphoma cells. Yet, in cells derived from a neuronal origin the pattern of expression of Myc targets was more complex. In a neuroepithelioma cell line that overexpresses c-myc, only some targets were expressed. In addition in neuroblastomas, in which N-myc is amplified and overexpressed, only ODC was overexpressed in all cell lines, while all other target genes were expressed in only some of the cell lines. The more complex expression pattern found for the Myc targets in neuroblastomas suggests that genes that were identified originally as targets for c-Myc regulation may be regulated by N-Myc, but other cell specific factors are also needed for transcription of the target genes.
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PMID:Involvement of Myc targets in c-myc and N-myc induced human tumors. 967

Normal intestinal mucosal growth requires polyamines that regulate expression of various genes involved in cell proliferation, growth arrest, and apoptosis. Our previous studies have shown that polyamine depletion stabilizes p53, resulting in inhibition of intestinal epithelial cell (IEC) proliferation, but the exact downstream targets of induced p53 are still unclear. The NDRG1 (N-myc downregulated gene-1) gene encodes a growth-related protein, and its transcription can be induced in response to stress. The current study tests the hypothesis that induced p53 inhibits IEC proliferation by upregulating NDRG1 expression following polyamine depletion. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with alpha-difluoromethylornithine not only induced p53 but also increased NDRG1 transcription as indicated by induction of the NDRG1 promoter activity and increased levels of NDRG1 mRNA and protein, all of which were prevented by using specific p53 siRNA and in cells with a targeted deletion of p53. In contrast, increased levels of cellular polyamines by ectopic expression of the ODC gene decreased p53 and repressed expression of NDRG1. Consistently, polyamine depletion-induced activation of the NDRG1-promoter was decreased when p53-binding sites within the NDRG1 proximal promoter region were deleted. Ectopic expression of the wild-type NDRG1 gene inhibited DNA synthesis and decreased final cell numbers regardless of the presence or absence of endogenous p53, whereas silencing NDRG1 promoted cell growth. However, overexpression of NDRG1 failed to directly induce cell death and to alter susceptibility to apoptosis induced by tumor necrosis factor-alpha/cycloheximide. These results indicate that NDRG1 is one of the direct mediators of induced p53 following polyamine depletion and that p53-dependent NDRG1 expression plays a critical role in the negative control of IEC proliferation.
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PMID:p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion. 1744 33


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