Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00790 (PGA)
 2,475 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclopentenone PGs (PGA and PGJ series) inhibit tumor cell proliferation in vitro and tumorigenesis in vivo via mechanisms that are at present poorly understood. The C6 rat glioma cell line synthesizes and secretes insulin-like growth factor-I (IGF-I), which is believed to act as an autocrine factor for these cells. PGA2 inhibits the proliferation of the C6 cells and causes an increase in the fraction of cells in the G1 phase of the cell cycle. The inhibition of cell proliferation by PGA2 is accompanied by a decrease in the abundance of IGF-I messenger RNA (mRNA). This regulation of IGF-I gene expression is specific, as the abundance of hypoxanthine-guanine phosphoribosyl transferase (HPRT) and ubiquitin mRNA is not significantly affected by PGA2. The repression of IGF-I gene expression is observed at PGA2 concentrations as low as 10 microM and is evident within 4 h after treatment of the C6 cells with PGA2. In addition to specifically regulating the expression of the IGF-I gene, PGA2 also decreases the abundance of cyclin D1 mRNA and increases the abundance of Waf1 mRNA. The inhibition of cell proliferation by PGA2 is partially reversed by coaddition of IGF-I, indicating partial dominance of IGF-I action over PGA2 action. To investigate the molecular basis for the regulation of IGF-I gene expression by PGA2, we developed a sensitive RT-PCR assay for IGF-I nuclear transcripts. A similar assay was developed for quantifying HPRT transcripts, which were used as a control. Treatment of the C6 cells with 20 microM PGA2 resulted in approximately a 6-fold decrease in IGF-I mRNA and IGF-I nuclear transcripts. In contrast, HPRT mRNA and nuclear transcript levels were not significantly affected by PGA2. These results indicate that the decrease in IGF-I mRNA abundance that occurs in response to PGA2 is caused largely by a decrease in IGF-I nuclear transcript levels. To identify the cis-acting element that mediates the effect of PGA2 on IGF-I transcription, C6 cells were transiently transfected with IGF-I/luciferase expression constructs in which luciferase transcription is driven by IGF-I P1 promoter fragments extending from -1711 to -328 or from -1114 to +328 relative to the beginning of exon 1. Treatment of cells with PGA2 in these transient transfection assays did not decrease luciferase activity. These results suggest that the cis-acting regulatory element required for the response to PGA2 is located outside the -1711 to +328 promoter interval.
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PMID:Prostaglandin A2 specifically represses insulin-like growth factor-I gene expression in C6 rat glioma cells. 904 99

Cyclopentenone prostaglandins exhibit unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. Recently the dienone prostaglandin, Delta(12)-PGJ(2), was shown to preferentially inhibit ubiquitin isopeptidase activity of the proteasome pathway. It is theorized that isopeptidase inhibition and general cytotoxicity of prostaglandins depend on olefin-ketone conjugation, electrophilic accessibility, and the nucleophilic reactivity of the endocyclic beta-carbon. Delta(12)-PGJ(2), which contains a cross-conjugated alpha,beta-unsaturated ketone, was a potent inhibitor of isopeptidase activity, whereas PGA(1) and PGA(2) with simple alpha,beta-unsaturated pentenones were significantly less potent and PGB(1) with a sterically hindered alpha,beta-unsaturated ketone was inactive. To further investigate the proposed mechanism, punaglandins, which are highly functional cyclopentadienone and cyclopentenone prostaglandins chlorinated at the endocyclic alpha-carbon position, were isolated from the soft coral Telesto riisei. They were then assayed for inhibition of ubiquitin isopeptidase activity and antineoplastic effects. The punaglandins were shown to inhibit isopeptidase activity and exhibit antiproliferative effects more potently than A and J series prostaglandins. Also, the cross-conjugated dienone punaglandin was more potent than the simple enone punaglandin. The ubiquitin-proteasome pathway is a vital component of cellular metabolism and may be a suitable target for antineoplastic agents. These newly characterized proteasome inhibitors may represent a new chemical class of cancer therapeutics.
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PMID:Punaglandins, chlorinated prostaglandins, function as potent Michael receptors to inhibit ubiquitin isopeptidase activity. 1505 3

Epigenetic changes including DNA methylation caused by environmental exposures may contribute to the heterogeneous inflammatory response in asthma. Here we investigate alterations in DNA methylation of purified blood monocytes that are associated with inflammatory phenotypes of asthma. Peripheral blood was collected from adults with eosinophilic asthma (EA; n = 21), paucigranulocytic asthma (PGA; n = 22), neutrophilic asthma (NA; n = 9), and healthy controls (n = 10). Blood monocytes were isolated using ficoll density gradient and immuno-magnetic cell separation. Bisulfite converted genomic DNA was hybridized to Illumina Infinium Methylation27 arrays and analyzed for differential methylation using R/Bioconductor packages; networks of gene interactions were identified using the STRING database. Compared with healthy controls, differentially methylated CpG loci were identified in EA (n = 413), PGA (n = 495), and NA (n = 89). We found that 223, 237, and 72 loci were significantly hypermethylated in EA, PGA, and NA, respectively. Nine genes were common to all three phenotypes and showed increased methylation in asthma. Three pathway networks were identified in EA, involved in purine metabolism, calcium signaling, and ECM-receptor interaction. In PGA, two networks were identified, involved in neuroactive ligand-receptor interaction and ubiquitin mediated proteolysis. In NA, one network was identified involving sFRP1 as a key node, over representing the Wnt signaling pathway. We have identified characteristic alterations in DNA methylation that are associated with inflammatory phenotypes of asthma and may contribute to the disease mechanisms. This network-based characterization may help in the development of epigenetic biomarkers and therapeutic targets for asthma.
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PMID:Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma. 2514 14