Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guanine nucleotide binding proteins (G proteins) are regulatory molecules that couple membrane receptors to effector systems such as adenylate cyclase and phospholipase C. The alpha subunits of G proteins bind to guanosine 5'-diphosphate (GDP) in the unstimulated state and guanosine 5' triphosphate (GTP) in the active state. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a specific inhibitor of inosine monophosphate (IMP) dehydrogenase, decreases guanylate synthesis from IMP in HL-60 promyelocytic leukemia cells and depletes intracellular guanine nucleotide pools. This study demonstrates that treatment of HL-60 cells with tiazofurin is associated with a fourfold increase in membrane binding sites for the nonhydrolyzable analogue GDP beta S. This increase in binding sites was associated with a 3.2-fold decrease in GDP beta S binding affinity. Similar findings were obtained with GTP gamma S. These effects of tiazofurin treatment on guanine nucleotide binding were also associated with decreased adenosine diphosphate-ribosylation of specific G protein substrates by cholera and pertussis toxin. The results further demonstrate that tiazofurin treatment results in inhibition of G protein-mediated transmembrane signaling mechanisms. In this regard, stimulation of adenylate cyclase by prostaglandin E2 was inhibited by over 50% in tiazofurin-treated cells. Furthermore, tiazofurin treatment resulted in inhibition of N-formylmethionylleucylphenylalanine-induced stimulation of phospholipase C. Taken together, these results indicate that tiazofurin acts at least in part by inhibiting the ability of G proteins to function as transducers of intracellular signals.
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PMID:Effects of tiazofurin on guanine nucleotide binding regulatory proteins in HL-60 cells. 196 38

The purpose of this study was to elucidate the behavior of signal transduction activity in rat and human carcinoma cells. Signal transduction activity was measured by the steady-state activity of the three enzymes involved in the conversion of 1-phosphatidylinositol (PI) to IP3, PI 4-kinase, PI 4-phosphate 5-kinase, and phospholipase C activities were measured by our methods. The results indicate that the steady-state activities of the three signal transduction enzymes and the end-product, IP3, were up-regulated in a transformation- and progression-linked fashion. In rat liver PI kinase, PIP kinase and PLC activities were 0.4, O.04, and 800 nmol/hour/mg protein, respectively. PI and PIP kinase and PLC activities were increased 2- to 8-fold in five rat hepatomas and 29-, 45-, and 4-fold, respectively, in rapidly growing hepatoma 3924A. PI and PIP kinase activities as compared to normal ovary were elevated in human ovarian epithelial carcinomas (4- and 3-fold) and in OVCAR-5 cells in culture (31- and 11-fold). Compared to normal breast parenchymal cells, PI and PIP kinase activities were increased in human breast carcinoma cells (96- and 16-fold). When breast carcinoma cells were plated and expressed their neoplastic proliferative program. IP3 concentration increased 20-fold in early log phase: PI and PIP kinase activities increased 11-fold in mid log phase: PLC activity did not change throughout. PI and PIP kinase activities in bone marrow had short half-lives (t1/2 = 8 minutes) but PLC had a long one (t1/2 > 6 hours). The elevated signal transduction activity was down-regulated by the anti-cancer drug, tiazofurin, and also by quercetin, an inhibitor of PI kinase. The addition of these drugs to cultured carcinoma cells reduced the IP3 concentration, and the cells were killed. These integrated studies are the first showing that signal transduction activity is stringently linked with transformation and progression in rat and human solid tumors and carcinoma cells. Down-regulation (by tiazofurin) or inhibition of PI and PIP kinase activities (by quercetin) in human carcinoma cells led to a marked reduction of IP3 concentration and to cell death. Tiazofurin and quercetin may be useful in the treatment of carcinomas with increased signal transduction capacity.
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PMID:Increased signal transduction activity and down-regulation in human cancer cells. 904