Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor yet identified. This peptide plays an important role in the regulation of arterial tone, in part through its interaction with endogenous vasodilator compounds. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs), we determined the effects of prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 on ET-1 synthesis and secretion from cultured bovine aortic endothelial cells and on ET-1 action in aortic smooth muscle cells. Both PGE2 and PGI2 (vasodilator prostaglandins) caused an approximately 40% inhibition of basal ET-1 secretion and a 50% inhibition of serum-stimulated ET-1 secretion in a dose-related and time course fashion. In contrast, the vasoconstrictor prostaglandin, thromboxane A2, had no effect on ET-1 secretion. PGE2 and PGI2 similarly inhibited the basal production of new ET-1 protein (translation) by 40-50% and inhibited the basal steady-state mRNA expression of ET-1 in bovine aortic endothelial cells by 60-70%. Both prostaglandins also caused an approximately 55% inhibition of ET-1 transcription, as shown by chloramphenicol acetyltransferase reporter studies. PGE2 and PGI2 strongly stimulated cGMP generation; both the PG stimulation of cGMP and the inhibition of ET-1 secretion and translation were reversed by LY83583, a general inhibitor of cGMP generation. The PG-induced inhibition of ET-1 secretion and translation was also reversed by KT5823, an inhibitor of cGMP-dependent protein kinase, but not by (Rp)-adenosine cyclic 3':5'-monophosphate, an inhibitor of protein kinase A activation. PGE2 and PGI2 also inhibited both basal and ET-1-stimulated DNA synthesis in aortic smooth muscle cells by approximately 45% through a cGMP-dependent mechanism. Therefore, two endogenous PGs, known to be important vasodilators in vivo, significantly inhibit the transcription, translation, secretion, and action of ET-1. We propose that the vasodilator action of the PGs results, in part, from their ability to inhibit the production of this potent vasoconstrictor.
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PMID:Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells. 816 94

Nitric oxide (NO) regulates the expression of multiple genes but in most cases its precise mechanism of action is unclear. We used baby hamster kidney (BHK) cells, which have very low soluble guanylate cyclase and cGMP-dependent protein kinase (G-kinase) activity, and CS-54 arterial smooth muscle cells, which express these two enzymes, to study NO regulation of the human fos promoter. The NO-releasing agent Deta-NONOate (ethanamine-2,2'-(hydroxynitrosohydrazone)bis-) had no effect on a chloramphenicol acetyltransferase (CAT) reporter gene under control of the fos promoter in BHK cells transfected with an empty vector or in cells transfected with a G-kinase Ibeta expression vector. In BHK cells transfected with expression vectors for guanylate cyclase, Deta-NONOate markedly increased the intracellular cGMP concentration and caused a small (2-fold) increase in CAT activity; the increased CAT activity appeared to be from cGMP activation of cAMP-dependent protein kinase. In BHK cells co-transfected with guanylate cyclase and G-kinase expression vectors, CAT activity was increased 5-fold in the absence of Deta-NONOate and 7-fold in the presence of Deta-NONOate. Stimulation of CAT activity in the absence of Deta-NONOate appeared to be largely from endogenous NO since we found that: (i) BHK cells produced high amounts of NO; (ii) CAT activity was partially inhibited by a NO synthase inhibitor; and (iii) the inhibition by the NO synthase inhibitor was reversed by exogenous NO. In CS-54 cells, we found that NO increased fos promoter activity and that the increase was prevented by a guanylate cyclase inhibitor. In summary, we found that NO activates the fos promoter by a guanylate cyclase- and G-kinase-dependent mechanism.
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PMID:Nitric oxide regulation of gene transcription via soluble guanylate cyclase and type I cGMP-dependent protein kinase. 1009 32

We tested the hypothesis that protein kinase (PK)G activation in response to nitric oxide ((*)NO) mediates tumor necrosis factor (TNF)-alpha-induced activation of the transcription factor activating protein-1 (AP-1) in pulmonary microvessel endothelial monolayers (PEM). The DNA-binding activity of AP-1 was assessed using the electrophoretic mobility shift assay. TNF treatment (1,000 U/ml) for 4 h induced a significant increase in DNA binding of AP-1. The effects of TNF were prevented by the superoxide radical scavenger superoxide dismutase (SOD) (100 U/ml), the (*)NO synthase inhibitor aminoguanidine (100 microM), the guanylate cyclase inhibitor ODQ (100 microM), and the PKG inhibitors KT5823 (1 microM) and 8-bromo-cyclic guanosine monophosphate (cGMP)-thioate (100 microM). Spermine-NO (1 microM) and L-arginine (400 microM) prevented the aminoguanidine-induced ablation of AP-1 activation in response to TNF. Phosphorylation of H-Arg-Lys-Ile-Ser-Ala-Ser-Glu-Phe-Asp-Arg-Pro-Leu-Arg-OH (BPDEtide), a specific substrate for PKG, measured the activity of cGMP-dependent protein kinase (PKG). TNF for 0.5 h induced an increase in PKG activity that was prevented by aminoguanidine, ODQ, KT5823, and 8-bromo-cGMP-thioate; however, SOD had no effect. The PKG agonist 8-bromo-cGMP (100 microM), when given alone, increased PKG activity but induced significant DNA-binding activity of AP-1 only when given in the ODQ + TNF Group. SIN-1 (1 mM, a peroxynitrite agonist) increased DNA-binding activity of AP-1. SOD prevented SIN-1-induced AP-1 activation, a response similar to that of the SOD + TNF Group. PEM were transfected with the chloramphenicol acetyltransferase (CAT) reporter plasmid pBLCAT2, which contains a regulation sequence responsive to AP-1. The pharmacologic profile of TNF-induced CAT activity was identical to TNF-induced DNA binding by AP-1. Thus, TNF-induced AP-1-dependent gene transcription is modulated by (*)NO-dependent mediated activation of PKG.
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PMID:Tumor necrosis factor-alpha-induced activating protein-1 activity is modulated by nitric oxide-mediated protein kinase G activation. 1061 72