Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro and in vivo experiments were conducted to determine the effects of the protein phosphatase (PPase) inhibitors sodium fluoride (fluoride), sodium orthovanadate (vanadate), and lithium chloride on nonspecific cytotoxic cell (NCC) lysis of target cells. Both vanadate and fluoride stimulated NCC activity. Lithium chloride had no effects. Optimum enhancement for "normal" NCC was at low effector:target cell ratios and at least 30 min treatment was required to achieve maximum activation effects. Fluoride, but not vanadate activation effects were largely reversible. Vanadate, 2.5-10 mM, produced a 5-10-fold increase in cytotoxicity at 25:1 E:T, whereas less than twofold increases were produced by these concentrations at 100:1. NCC activity from "stressed" fish that had essentially no cytotoxic activity were also activated by vanadate. In vitro preincubation of NCC with 10-20 mM fluoride or 2.5-10 mM vanadate produced up to a 20-fold increase in stressed cytotoxicity. Combined treatments with 2.5 mM vanadate and 20 mM fluoride produced even greater responses. In vivo responses to vanadate were also determined. Treatment of catfish by immersion in 50 microM vanadate produced significant increases in cytotoxicity by 24-48 h posttreatment. Activation of cytotoxicity was not accompanied by increases in percentage of NCC (small lymphocyte content) or in total cell numbers in anterior kidney tissue. These studies indicated that levels of NCC activity are partially regulated by control of dephosphorylation of membrane proteins. Inability of NCC from stressed fish to lyse IM-9 target cells was reversed (probably) by disruption of an equilibrium between kinase and phosphatase activities. Normal NCC were "superactivated" only under conditions were they were in limiting numbers. These data show that phosphatases must be considered as active participants in regulation of signal transduction processes.
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PMID:Role of protein phosphatases in the regulation of nonspecific cytotoxic cell activity. 808 15

We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3beta. In addition, the GSK-3beta inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3beta-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3beta and Foxo transcription factors.
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PMID:Protein breakdown in muscle from burned rats is blocked by insulin-like growth factor i and glycogen synthase kinase-3beta inhibitors. 1580 92