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

Many oncogene products are protein kinases and signals are transduced via phosphorylation of proteins. Similarly, protein-dephosphorylation may play a critical role in malignant cell transformation. We have cloned two catalytic subunits of ser/thr protein phosphatase (PP) type 2A, PP2A alpha, and PP2A beta, from a rat liver cDNA library. Both cDNAs encode peptides of 309 amino acids with a difference of only 8 amino acids between the two. All primary hepatocellular hyperplastic nodules or carcinomas, which were induced by a food carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline, showed up-regulation of expression of the mRNAs of both PP2A alpha and PP2A beta. NIH3T3 cell transformants obtained by introducing activated c-raf, ret-II or Ki-ras oncogenes also showed high levels of PP2A alpha transcripts. Okadaic acid, a non-TPA type tumor promoter, was found to be a potent inhibitor of PP1 and PP2A. Its IC50 for PP1 was much higher than that for PP2A with phosphorylase a as a substrate. When raf and ret-II transformants were cultured with okadaic acid at 8 ng/ml for 2 days, both transformants became flattened and showed strict contact inhibitions. This flat cell morphology was stable for at least one month in the presence of okadaic acid, but in its absence, the cells reverted to their original transformed shape within 7-10 days. Colony formation by raf and ret-II transformants in soft agar was inhibited dose-dependently by okadaic acid; very few colonies grew in the presence of the acid at 8 ng/ml. Okadaic acid had less effect on a transformant of the Ha-ras gene, causing only 50% inhibition of colony formation at 8 ng/ml. The role of protein phosphatases in cellular transformation by certain oncogenes is suggested.
 ...
PMID:Role of protein phosphatases in malignant transformation. 256 81

A cDNA clone coding for an isotype of the catalytic subunit of rat phosphoprotein phosphatase 2A was isolated. The deduced amino acid sequence of the clone was different at 8 positions from that of rat phosphatase 2A alpha determined in a previous study. The deduced amino acid sequence of the clone was, however, identical to that of human phosphatase 2A beta and differed only at one position from that of rabbit 2A beta. Thus, the isolated cDNA was identified as a clone coding for rat phosphatase 2A beta. Using a 2A beta specific probe, two kinds of transcripts were detected in rat liver: a major 2.0 kb mRNA transcript and a minor 1.4 kb mRNA transcript. These transcripts were both greatly increased in rat liver tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) regardless of the carcinoma or hyperplastic nodule.
 ...
PMID:Molecular cloning of rat phosphoprotein phosphatase 2A beta cDNA and increased expressions of phosphatase 2A alpha and 2A beta in rat liver tumors. 284 37

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.
 ...
PMID:Redox regulation of Cdc25B by cell-active quinolinediones. 1615 9

Cdc25B protein phosphatase represents an attractive potential therapeutic target for small molecule intervention because of its central role in positively regulating cyclin dependent kinases and thus cell proliferation, as well as its elevated levels observed in many human tumors. Among the most potent previously identified Cdc25 inhibitors have been quinoline quinones, which have a rich legacy as therapeutic agents but have also been associated with nonspecific interactions. In this study, we have interrogated the structure-activity relationship of a focused series of C2-, C3-, or C4-modified quinoline-5,8-quinones on Cdc25B inhibition in vitro. Substitution at the C3-position in this small chemical series were slightly superior to substitutions at the C3-position. For all compounds, recombinant human Cdc25B was approximately 5-fold more sensitive compared to recombinant human PTP1B. Two compounds inhibited HeLa cell growth with IC50 values of approximately 2 microM. Consistent with other para-quinones, some members of this series generated intracellular reactive oxygen species and the in vitro enzyme inhibition was mitigated by addition of reductants or catalase. These results indicate that chemical modifications on the pyridine core are tolerated, providing additional sites for future structural modification of this biologically active pharmacophore.
 ...
PMID:Biological evaluation of newly synthesized quinoline-5,8-quinones as Cdc25B inhibitors. 1678 52

Protein phosphorylation plays critical roles in many regulatory mechanisms controlling cell activities and thus involved in various diseases. The cellular equilibrium of phosphorylation is regulated through the actions of protein kinases and phosphatases. Therefore, these regulatory proteins have emerged as promising targets for drug development. In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs. Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition. NSC-87877 effectively inhibited DUSP26-mediated dephosphorylation of p38, a member of mitogen-activated protein kinase (MAPK) family. Since DUSP26 is involved in survival of anaplastic thyroid cancer (ATC) cells, NSC-87877 could be a therapeutic reagent for treating ATC.
 ...
PMID:NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26). 1923 43

The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.
 ...
PMID:Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates. 2180 42