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

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

Proinflammatory cytokines and prostaglandins play key roles in term and preterm human labor. The expression of the prostaglandin synthetic enzyme cyclooxygenase (COX)-2 and cytokines IL-1beta and IL-8 increases within the uterus at the time of labor, and each is regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). In addition to its role in driving inflammation, COX-2 may also synthesize 15-deoxy-Delta (12, 14)-prostaglandin J(2) (15d-PGJ(2)), an antiinflammatory cyclopentenone prostaglandin (cyPG), which acts in some cells as an agonist of peroxisome proliferator-activated receptors (PPARs). We found that PPARalpha and -gamma proteins are expressed in both amnion epithelial and myometrial cells, but synthetic PPAR agonists could not inhibit NF-kappaB activity or COX-2 expression. 15d-PGJ(2) inhibited NF-kappaB activity and COX-2 expression in both cell types. This was unaffected by a PPAR antagonist and could be mimicked by the cyPG PGA(1) but not 9,10-dihydro-15d-PGJ(2) in which the cyclopentenone ring is disrupted. This shows that, in amnion and myometrium, inhibition of NF-kappaB activity and COX-2 expression by 15d-PGJ(2) is independent of PPARs and requires the cyclopentenone ring. We further show that 15d-PGJ(2) acts at multiple levels in the NF-kappaB pathway: blocking inhibitor of kappaBalpha degradation by repressing inhibitor of kappaB kinase activation and the 26S proteasome and also repressing NF-kappaB DNA binding and phosphorylation. Our data suggest that PPARs are unlikely to play a role in the regulation of either NF-kappaB or COX-2 in human amnion and myometrium. Targeting of NF-kappaB is a potential therapeutic strategy in preterm labor. PPAR agonists are unlikely to be effective in this context, but cyPGs may have potential.
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PMID:15-Deoxy-{delta}12,14-prostaglandin j2 inhibits interleukin-1{beta}-induced nuclear factor-{kappa}b in human amnion and myometrial cells: mechanisms and implications. 1575 49

15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) is a peroxisome-activated proliferator receptor-gamma (PPARgamma) agonist which contains an alpha,beta-unsaturated electrophilic ketone involved in nucleophilic addition reactions to thiols. Here we studied its effect on hypoxia-inducible factor-1alpha (HIF-1alpha) in human proximal tubular cells HK-2. 15d-PGJ(2) induced stabilization of HIF-1alpha protein, without affecting HIF-1alpha mRNA levels or proteasome activity, leading to its nuclear accumulation and activation of HIF-induced transcription. Accumulation of HIF-1alpha was unaffected by selective PPARgamma blockade nor mimicked by the PPARgamma agonists ciglitazone and 9,10-dihydro-15d-PGJ(2). N-acetylcysteine, reduced glutathione (GSH) or dithiothreitol (i.e. agents that act as thiol reducing agents and/or increase the GSH content), but not reactive oxygen species (ROS) scavengers, prevented 15d-PGJ(2)-induced HIF-1alpha accumulation whereas the inhibitor of GSH synthesis buthionine sulfoximine cooperated with 15d-PGJ(2) to accumulate HIF-1alpha. Finally, HIF-1alpha expression was increased by the electrophilic alpha,beta-unsaturated compounds acrolein and PGA(2), but not by 9,10-dihydro-15d-PGJ(2), which lacks the electrophilic cyclopentenone moiety. Taken together, these results point out to a new mechanism to increase pharmacologically the cell levels of HIF-1alpha through the electrophilic reaction of alpha,beta-unsaturated ketones with thiol groups.
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PMID:Accumulation of hypoxia-inducible factor-1alpha through a novel electrophilic, thiol antioxidant-sensitive mechanism. 1765 43