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)

Cell number is regulated by maintaining a balance between cell proliferation and cell death through apoptosis. Key regulators of this balance include the oncogene product c-Myc, which promotes either entry into the cell cycle or apoptosis [1]. Although the mechanism of c-Myc-induced apoptosis remains unclear, it is susceptible to regulation by survival factors [2,3] and can proceed through the interaction of Fas ligand (FasL) with its receptor, Fas [4]. Activated T lymphocytes are eliminated by an apoptotic process known as activation-induced cell death (AICD), which requires the transcriptional induction of FasL expression [5-7] and sustained levels of c-Myc [8]. The FasL promoter can be driven by c-Myc overexpression, and functional inhibitors of Myc and its binding partner, Max, inhibit the transcriptional activity of the FasL promoter [9,10]. We identified a non-canonical binding site (ATTCTCT) for c-Myc-Max heterodimers in the FasL promoter, which, when mutated, abolished activity in response to c-Myc. Exchange of the canonical c-Myc responsive elements (CACGTG) in the ornithine decarboxylase (ODC) promoter [11] with the non-canonical sequence in the FasL promoter generated an ODC-FasL promoter that was significantly more responsive to c-Myc than the wild-type ODC promoter. Our findings identify a precise physiological role for c-Myc in the induction of apoptosis as a transcriptional regulator of the FasL gene.
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PMID:A 'non-canonical' DNA-binding element mediates the response of the Fas-ligand promoter to c-Myc. 1105 Mar 89

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

5-fluorouracil (5-FU) is the major chemotherapeutic agent for treatment of colorectal carcinoma, but the molecular mechanisms of response and resistance are not understood completely. We therefore studied the 5-FU dose response and time course of gene expression transcriptome changes in colon carcinoma cell lines that are relatively sensitive to or resistant to 5-FU (RKO and HT29, respectively. We identified cellular pathways and corroborated functions of selected pathways. Expression of genes for polyamine biosynthesis, i.e., ornithine decarboxylase (ODC) and spermine and spermidine synthases, was repressed in the sensitive line, while the biosynthesis-inhibiting gene ODC antizyme was induced in the resistant line. The rate-limiting gene in catabolism, spermine/spermidine acetyltransferase, was induced in both lines. Polyamine levels showed corresponding drastic decreases after 5-FU treatment, and polyamine replenishment interfered with 5-FU-induced apoptosis. In the sensitive cells which have wild-type p53, the p53 gene and its downstream genes including p21/WAF1, mdm2, Fas, mic-1, EphA2, and ferredoxin reductase as well as genes in the tumor necrosis factor (TNF) pathway including TNF receptor 2 (TNFR2) were induced, but not Fas ligand (FasL). Exposure to exogenous FasL increased 5-FU-induced apoptosis, and anti-TNFR2 antibody, but not anti-TNFR1, partially protected the sensitive cells. Our combination of gene expression profiling and corroborative functional studies revealed that reduced polyamine levels, non-autocrine FasL originating exogenous to tumor cells, and induced TNFR2 are all functional mediators of apoptosis caused by 5-FU in colon carcinoma cells.
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PMID:Apoptotic response to 5-fluorouracil treatment is mediated by reduced polyamines, non-autocrine Fas ligand and induced tumor necrosis factor receptor 2. 1461 30

Polyamines, namely putrescine, spermidine, and spermine, are biogenic low-molecular-weight aliphatic amines which play essential roles in cell growth and proliferation. The aim of this study was to determine the effects of polyamines on the viability and development of porcine diploid parthenotes developing in vitro. The addition of 0.1 or 1.0 microM of putrescine, spermidine, or spermine, individually, to the culture medium did not enhance the development of 2-cell parthenotes to the blastocyst stage and did not change the total number of nuclei in the blastocysts. However, combined addition of these three compounds increased developmental rate to blastocyst and total cell numbers. Apoptosis in blastocyst stage parthenotes was decreased in the presence of exogenous polyamines. Real time PCR revealed that addition of polyamines to the culture media decreased the ratio of mRNA expression of Bak/Bcl-xL, Fas/Bcl-xL, and caspase 3, and enhanced mRNA expression of ornithine decarboxylase (ODC) and spermidine synthase, enzymes of polyamine biosynthesis. In the presence of L-alpha-difluoromethyl ornithine (an inhibitor of ODC) or cyclohexylamine (an inhibitor of spermidine synthase) development of porcine parthenotes decreased, apoptosis increased, and mRNA expression of the ratio of Bak/Bcl-xL and Fas/Bcl-xL, and caspase 3 increased. These results suggest that exogenous polyamines in the culture medium prevent apoptosis of porcine parthenotes and results in the net enhancement of porcine embryo viability.
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PMID:Polyamines inhibit apoptosis in porcine parthenotes developing in vitro. 1568 29