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)

The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.
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PMID:Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes. 254

Ornithine decarboxylase (ODC), the first enzyme in the biosynthesis of polyamines, is essential for the process of cellular proliferation. ODC is a typical delayed early gene, as its mitogenic activation requires ongoing protein synthesis in the stimulated cells. This study provides evidence that the immediate early c-Myc protein is a potential transactivator of the ODC gene. We demonstrate that overexpression of c-Myc results in efficient activation of the ODC promoter, whereas overexpression of Max exerts a repressive effect. Both effects depend on the presence of two evolutionary conserved CACGTG motifs found in the first intron of the ODC gene. Transactivation of the ODC promoter also requires the dimerization of c-Myc with Max. Interestingly, over-expression of USF, a member of the same family of proteins which efficiently binds these two CACGTG motifs, fails to transregulate the ODC promoter. Our data suggest that c-Myc and Max are potential transcriptional regulators of the ODC promoter.
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PMID:c-Myc and Max transregulate the mouse ornithine decarboxylase promoter through interaction with two downstream CACGTG motifs. 747 99

The c-myc oncogene c-Myc is commonly activated in cancer and transactivates gene expression by binding to CACGTG DNA sequences as a heterodimeric complex with Max. The ornithine decarboxylase (ODC), p53, prothymosin alpha and ECA39 promoters are transactivated by c-Myc, and are considered direct targets, as activation is mediated by CACGTG sequences. Interestingly, the c-Myc-responsive CACGTG sequences in the p53, prothymosin alpha, ECA39 and murine ODC genes are all downstream of the RNA CAP site, suggesting that downstream sequences are preferred c-Myc targets. Using a series of heterologous reporter constructs, we have tested the effects of position and orientation of c-Myc-responsive CACGTG sequences on c-Myc's ability to activate transcription. A single binding site conferred c-Myc-responsiveness independent of position and orientation, and over distances of 1.7 kbp. The extent of transactivation was not significantly influenced by position of the responsive elements. By contrast, the extent of transactivation was dependent upon the number of c-Myc binding sites. The results demonstrate that c-Myc activates transcription independent of position and orientation and that considerable flexibility exists in the interaction of c-Myc transactivation domains with the general transcription machinery.
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PMID:Position and orientation independent transactivation by c-Myc. 778 88

WI-38 cells can remain quiescent for long periods of time and still be induced to reenter the cell cycle by the addition of fresh serum. However, the longer these cells remain growth arrested, the more time they require to enter S phase. This prolongation of the prereplicative phase has been localized to a point early in G1, after the induction of "immediate early" G1 genes such as c-fos and c-jun but before maximal expression of "early" G1 genes such as ornithine decarboxylase (ODC). Understanding the molecular basis for ODC mRNA induction can therefore provide information about the molecular events which regulate the progression of cells out of long-term quiescence into G1 and subsequently into DNA synthesis. Studies utilizing electrophoretic mobility shift assays (EMSA) of nuclear extracts from short- and long-term quiescent WI-38 cells identified a region of the human ODC promoter at -491 bp to -474 bp which exhibited a protein binding pattern that correlated with the temporal pattern of ODC mRNA expression. The presence of a CACGTG element within this fragment, studies with antibodies against c-Myc and Max, the use of purified recombinant c-Myc protein in the mobility shift assay, and antisense studies suggest that these proteins can specifically bind this portion of the human ODC promoter in a manner consistent with growth-associated modulation of the expression of ODC and other early G1 genes following prolonged quiescence. These studies suggest a role for the c-Myc/Max protein complex in regulating events involved in the progression of cells out of long-term quiescence into G1 and subsequently into S.
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PMID:Regulation of human ornithine decarboxylase expression following prolonged quiescence: role for the c-Myc/Max protein complex. 782 33

Translocations or amplifications which activate members of the myc gene family are common in human cancer. c-Myc is a central regulator of normal cell proliferation and differentiation (Luscher and Eisenman, 1991; Marcu et al. 1992) and can induce apoptosis (Askew et al. 1991, 1993; Evan et al. 1992; Bissonette et al. 1992; Shi et al. 1992). c-Myc is a transcription factor (Amati et al. 1992; Kretzner et al. 1992), however, the targets regulated by c-Myc which mediate its activities are not known. Here, we discuss the role of the ornithine decarboxylase (ODC) gene as a direct transcriptional target of c-Myc and demonstrate a role for ODC enzyme activity in c-Myc-induced apoptosis.
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PMID:The role of ornithine decarboxylase in c-Myc-induced apoptosis. 789

c-Myc plays a central role in the regulation of cell cycle progression, differentiation, and apoptosis. However, the proteins which mediate c-Myc function(s) remain to be determined. Enforced c-myc expression rapidly induces apoptosis in interleukin-3 (IL-3)-dependent 32D.3 murine myeloid cells following IL-3 withdrawal, and this is associated with the constitutive, growth factor-independent expression of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis. Here we have examined the role of ODC in c-Myc-induced apoptosis. Enforced expression of ODC, like c-myc, is sufficient to induce accelerated death following IL-3 withdrawal. ODC induced cell death in a dose-dependent fashion, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, effectively blocked ODC-induced cell death. ODC-induced cell death was due to the induction of apoptosis. We also demonstrate that ODC is a mediator of c-Myc-induced apoptosis. 32D.3-derived c-myc clones have augmented levels of ODC enzyme activity, and their rates of death were also a function of their ODC enzyme levels. Importantly, the rates of death of c-myc clones were inhibited by treatment with DFMO. These findings demonstrate that ODC is an important mediator of c-Myc-induced apoptosis and suggest that ODC mediates other c-Myc functions.
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PMID:Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis. 806 8

The presence of a CACGTG element within a region of the human ornithine decarboxylase (ODC) promoter located at -491 to -474 base pairs 5' to the start site of transcription suggested that the c-Myc.Max protein complex may play a role in the regulation of ODC expression during growth. Electrophoretic mobility shift assays and methylation interference analysis showed that the nuclei of WI-38 cells expressing ODC contained proteins that bound to this region of the ODC gene in a manner that correlated with growth-associated ODC expression. Also, use of antibodies against c-Myc and Max and purified recombinant c-Myc and Max protein in the electrophoretic mobility shift assay confirmed that these proteins can specifically bind this portion of the human ODC promoter. Transient transfection studies showed that increase in the level of c-Myc and/or Max led to a significant enhancement of expression of a human ODC promoter-CAT reporter construct. Moreover, treatment of actively growing WI-38 cells with an antisense oligomer to c-Myc reduced the amount of endogenous protein complex formed and the amount of endogenous ODC mRNA expressed. These studies show that the c-Myc.Max protein complex plays a role in the transcriptional regulation of human ODC in vivo.
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PMID:Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex. 826 68

The role of the product of the c-myc protooncogene in the regulation of cellular proliferation and differentiation is well established. Recent reports that c-Myc can serve as a sequence-specific transcriptional activator have begun to elucidate the mechanism by which c-Myc exerts such a profound effect on the mitotic status of a cell. To identify a potential target gene for Myc-mediated trans-activation, we examined the regulation of the ornithine decarboxylase (ODC) gene by c-Myc. ODC is the first and rate-limiting enzyme involved in the synthesis of the polyamines and has been shown to be required for entry into and progression through the cell cycle. Using a conditionally active c-Myc-estrogen receptor chimeric protein, we found estrogen-dependent activation of ODC expression and enzymatic activity. The induction of ODC mRNA expression was not dependent upon de novo protein synthesis. These data suggest that one downstream pathway for Myc-directed cell cycle control is the induction of ODC expression.
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PMID:c-Myc induces the expression and activity of ornithine decarboxylase. 829 93

Constitutive c-myc expression suppresses cell cycle arrest, promotes entry into S phase, and results in the growth factor-independent expression of ornithine decarboxylase (ODC; EC 4.1.1.17). The ODC gene contains a conserved repeat of the Myc binding site, CACGTG, in intron 1. In this report, we demonstrate that c-Myc is a potent transactivator of ODC promoter-reporter gene constructs in fibroblasts that requires the CACGTG repeat. These sites conferred Myc responsiveness on heterologous promoter constructs, suggesting that ODC is regulated by Myc at the level of transcription initiation. Analysis of deletion and point mutants of c-myc revealed that domains required for transactivation of the ODC promoter did not include the leucine zipper of the Myc protein. This suggests that Myc may interact with transcription factors other than Max to transactivate the ODC gene.
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PMID:The ornithine decarboxylase gene is a transcriptional target of c-Myc. 835 88

We have analysed relative DHFR gene copy numbers in nine cell lines of various cell type and species origins. The cells studied expressed either low, low and inducible or constitutively elevated levels of c-Myc protein. DHFR gene amplification was observed only when c-Myc protein levels were upregulated. The amplification of the DHFR gene was transient in inducible cell lines. Cell lines exhibiting constitutively deregulated c-Myc protein levels, however, showed both DHFR gene amplification and ongoing rearrangements of the DHFR locus. In contrast, the relative gene copy numbers of ribonucleotide reductase R1 subunit, ornithine decarboxylase, syndecan 2, glyceraldehyde-3-phosphate-dehydrogenase, and cyclin C remained unaffected irrespective of c-Myc protein levels, suggesting a locus-specific genomic instability of the DHFR gene in cells with deregulated c-Myc protein levels. Overall, the results of the present study support the notion that DHFR gene amplification as a consequence of c-Myc deregulation may occur in a variety of cell lines irrespective of their cell type and species origins.
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PMID:c-Myc overexpression associated DHFR gene amplification in hamster, rat, mouse and human cell lines. 857 Feb 5


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