Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent rodent carcinogen and suspected human carcinogen, are mediated by the Ah receptor, a ligand-activated transcription factor. Genes altered by TCDD at the transcriptional level in the transformed human keratinocyte cell line SCC-12F include cytochrome P4501A1 (CYP1A1), CYP1B1, transforming growth factor-beta 2, and plasminogen activator inhibitor-2 (PAI-2). Plasminogen activators are serine proteases involved in a number of cell processes, including migration, proliferation, growth factor activation, and tumorigenesis. In this study we investigated the effect of TCDD on other members of the plasminogen activator family. We report that in addition to the transcriptional induction of PAI-2, treatment of SCC-12F cells with 10 nM TCDD also resulted in an increase in urokinase-plasminogen activator (u-PA) mRNA. Induction of u-PA mRNA was maximal by 12 hr and remained approximately twofold above control levels for the 48-hr assay period. Transcription of u-PA was not altered by TCDD as determined by nuclear runoff analysis. Instead, induction of u-PA occurred as a result of a stabilization of the u-PA mRNA following TCDD treatment. Tissue-plasminogen activator and PAI-1 expression were not altered by TCDD. Thus, TCDD acts through different mechanisms in SCC-12F cells to induce both a plasminogen activator and a specific inhibitor of plasminogen activation. These results, together with our earlier results showing an induction of TGF-alpha by TCDD as a result of a stabilization of the TGF-alpha mRNA, demonstrate the importance of both transcriptional and post-transcriptional events in the regulation of gene expression by TCDD.
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PMID:Post-transcriptional stabilization of urokinase plasminogen activator mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a human keratinocyte cell line. 759 8

The regulatory effects of transforming growth factor (TGF)-alpha on phospholipase A(2) (PLA(2)) isozymes contributing to prostaglandin generation in rat gastric epithelial RGM1 cells were examined. Stimulation with TGF-alpha for 24 h time-dependently induced prostaglandin E(2) generation with an increase in cyclo-oxygenase-2 protein. The TGF-alpha-induced prostaglandin E(2) generation was suppressed by NS-398, a cyclo-oxygenase-2 inhibitor. TGF-alpha stimulated the activity and the protein synthesis of cytosolic PLA(2) (cPLA(2)). A time-dependent increase in cPLA(2) protein occurred in parallel with PGE(2) generation, which was inhibited by methyl arachidonyl fluorophosphonate (MAFP), a cPLA(2) inhibitor. However, no change in activity of secretory PLA(2) or Ca(+2)-independent PLA(2) was observed in the TGF-alpha-stimulated cells. Stimulation with the Ca(2+) ionophore A23187 for 10 min induced MAFP-sensitive arachidonic acid liberation. Interestingly, preincubation with TGF-alpha for 24 h diminished A23187-stimulated arachidonic acid liberation despite the increase in cPLA(2) protein. Under the conditions, TGF-alpha was found to increase p11, an endogenous cPLA(2) suppressor, also known as annexin II light chain. The TGF-alpha-induced increase in p11 was suppressed by tyrphostin AG1478, an inhibitor of tyrosine kinase of epidermal growth factor receptor, which was also found to restore the inhibition by TGF-alpha of A23187-stimulated arachidonic acid liberation. However, TGF-alpha did not alter protein levels of annexin II heavy chain. These results suggest that TGF-alpha stimulates prostaglandin generation through an increase in cPLA(2), the hydrolytic action of which may be under the control of p11.
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PMID:Transforming growth factor-alpha stimulates prostaglandin generation through cytosolic phospholipase A(2) under the control of p11 in rat gastric epithelial cells. 1105 23

Although transforming growth factor (TGF)-alpha, a member of the epidermal growth factor (EGF) family, has been shown to protect neurons against excitotoxic and ischemic brain injuries, its mechanism of action remains unknown. In the present study, we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF-alpha rescues neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxic death, with the obligatory presence of astrocytes. Because neuronal tissue-type plasminogen activator (t-PA) release was shown to potentiate NMDA-induced excitotoxicity, we observed that TGF-alpha treatment reduced NMDA-induced increase of t-PA activity in mixed cultures of neurons and astrocytes. In addition, we showed that although TGF-alpha induces activation of the extracellular signal-regulated kinases (ERKs) in astrocytes, it failed to activate p42/p44 in neurons. Finally, we showed that TGF-alpha, by an ERK-dependent mechanism, stimulates the astrocytic expression of PAI-1, a t-PA inhibitor, which mediates the neuroprotective activity of TGF-alpha against NMDA-mediated excitotoxic neuronal death. Taken together, we indicate that TGF-alpha rescues neurons from NMDA-induced excitotoxicity in mixed cultures through inhibition of t-PA activity, involving PAI-1 overexpression by an ERK-dependent pathway in astrocytes.
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PMID:Transforming growth factor alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity. 1249 May 42