Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Okadaic acid, a protein phosphatase inhibitor, is a strong tumor promoter which activates protein phosphorylation. Because another activator of protein phosphorylation, phorbol esters, stimulates hematopoietic differentiation, we sought to determine whether okadaic acid could also induce the differentiation of the human leukemic cell line U937. Differentiation was assessed by measuring changes in the following: mRNA levels, cell growth, morphology, cell surface markers, and the ability to induce superoxide. We found that okadaic acid treatment of U937 cells induces immediate increases in total cellular levels of both c-jun and c-fos mRNAs. Nuclear run-on experiments demonstrate that initial increases are secondary to increases in transcription, whereas latter changes may be secondary to mRNA stabilization. Like phorbol esters, okadaic acid treatment also activates AP-1 enhancer activity and induces the phosphorylation of c-Jun protein. Approximately 6-12 hours after treatment with okadaic acid, mRNA levels of c-myc, p34cdc2, and p58GTA, two cell cycle regulated protein kinases, decrease. Okadaic acid inhibits the growth of U937 cells, induces changes in nuclear morphology, stimulates increases in Mac-1 and Leu 11 surface antigens, and induces these cells to produce superoxide. These changes, taken together, suggest that U937 cells have been induced by okadaic acid to differentiate towards a more mature cell type.
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PMID:Induction of differentiation and c-jun expression in human leukemic cells by okadaic acid, an inhibitor of protein phosphatases. 131 24

Cytokines such as interleukin-1, which are found in the brain after trauma, regulate expression of nerve growth factor (NGF) mRNA and protein in hippocampal cultures. We have investigated possible mechanisms by which Il-1 beta regulates NGF in hippocampal cells. The induction of NGF mRNA by Il-1 beta was blocked by a receptor antagonist indicating that this effect is receptor mediated. Il-1 beta elicited a dramatic induction of c-fos mRNA and a slight elevation of c-jun mRNA in a time dependent manner which may allow for a role in the induction of NGF mRNA expression. We examined whether specific second messenger pathways were involved in mediating the action of Il-1 beta in the hippocampus. Activation of cAMP with forskolin or treatment with 8-Br-cAMP had no effect on NGF mRNA levels. Moreover, exposure of hippocampal cultures to Il-1 beta evoked no change in cAMP levels, indicating that this second messenger system played little or no role in the regulation of NGF expression by Il-1 beta in these cells. Further, interleukin-1 elicited no change in membrane inositol phosphate turnover, nor did it affect intracellular calcium levels. Treatment of cell cultures with the phorbol ester PMA elicited an increase in NGF mRNA, suggesting that activation of protein kinase C (PKC) may mediate NGF mRNA expression. However, prolonged treatment of cultures with PMA to desensitize PKC did not eliminate the Il-1 beta induction of NGF mRNA. Il-1 beta, therefore, did not appear to activate NGF expression via cAMP, Ca2+, or a PKC isoform that is downregulated by prolonged PMA treatment. However, a phosphorylation event may be involved in the signal transduction mechanism, as treatment with okadaic acid to inhibit protein phosphatase 2a potentiated the induction of NGF mRNA by Il-1 beta. The results presented indicate that Il-1 beta acts via its receptor to induce a rise in NGF expression. Identification of the specific second messenger pathway has remained elusive; however, a phosphorylation event appears to be intermediary. Moreover, the induction of c-fos and c-jun may represent a final common path in activation of NGF gene expression by different signals such as Il-1 beta and PMA.
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PMID:Mechanisms of nerve growth factor mRNA regulation by interleukin-1 beta in hippocampal cultures: role of second messengers. 133 37

Okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, induces differentiation in human MCF-7, AU-565, and MB-231 breast tumor cells. In MCF-7 cells, OA elicited within 5 min an increase in the levels of a set of phosphorylated cellular proteins, within hours expression of the early response genes junB, c-jun, and c-fos, and within days manifestation of differentiation. Differentiation was also induced by two related protein phosphatase inhibitors, but not by an inactive OA derivative or by an inhibitor that penetrates epithelial cells poorly. These results indicate that OA and related agents can induce tumor breast cell differentiation, and this induction is correlated with their ability to inhibit PPH 1 and 2A.
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PMID:Differentiation induction in human breast tumor cells by okadaic acid and related inhibitors of protein phosphatases 1 and 2A. 133 63

The widely accepted hypothesis of vanadate action on cells postulates that this ion inhibits protein phosphatase(s) that dephosphorylates protein phosphotyrosine residues. This inhibition causes tyrosine hyperphosphorylation of cell proteins followed by changes in physiological action of phosphoproteins resulting in stimulation of cell proliferation, expression of protooncogenes, and transient cell transformation. We have found that treatment of human ovary carcinoma (CaOv) cells with vanadate causes the increase in total protein phosphorylation from 1.5- to 2.0-fold whereas the ratio between phosphoserine, phosphothreonine, and phosphotyrosine content remains unchanged. At the same time, enhancement of c-myc gene expression (not c-fos) was observed. Hence, the increase in the ratio of phosphotyrosine to phosphoserine and phosphothreonine is not an obligatory intermediate stage before vanadate-dependent activation of c-myc expression.
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PMID:Expression of c-myc gene in human ovary carcinoma cells treated with vanadate. 210 2

Recent studies indicate multiple mechanisms are involved in Ca2+ stimulation of gene expression. We have used cell-permeable, specific inhibitors of calmodulin-dependent protein kinases (CaM kinases) and phosphatase (calcineurin) to investigate the involvement of these enzymes in transcriptional regulation of three immediate early genes in PC12 cells stimulated with A23187 or KCl. Preincubation of PC12 cells with the CaM kinase inhibitor KN-62 blocked autophosphorylation of CaM kinase II in response to stimulation by the Ca2+ ionophore A23187. KN-62 treatment also resulted in a 60-70% inhibition of Ca(2+)-dependent transcription of c-fos, NGFI-A (zif 268), and NGFI-B (nur 77) as assessed by either Northern or nuclear run-on analyses. Preincubation with the calcineurin inhibitors FK-506 or cyclosporin A strongly enhanced expression of NGFI-A and blocked transcription of NGFI-B, but it had no significant effect on Ca(2+)-stimulated transcription of c-fos. Both FK-506 and KN-62 were specific for Ca(2+)-stimulated transcription as neither effected transcription in response to forskolin or phorbol ester (12-O-tetradecanoylphorbol-13-acetate) treatment. This is the first report of CaM kinase and calcineurin involvement in transcriptional regulation of NGFI-A and NGFI-B. Activation of CaM kinases and calcineurin, in response to elevated intracellular Ca2+, would exert antagonistic effects on transcription of NGFI-A. Since inhibition of either the kinase or phosphatase decreased transcription of NGFI-B by 60-90%, this suggests that each enzyme is necessary but not sufficient for Ca2+ stimulation. These results indicate that CaM kinases and calcineurin can mediate broad and complex regulation of Ca(2+)-stimulated gene expression.
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PMID:Roles of calmodulin-dependent protein kinases and phosphatase in calcium-dependent transcription of immediate early genes. 752 Apr 33

SHPTP2 is a ubiquitously expressed tyrosine-specific protein phosphatase that contains two amino-terminal Src homology 2 (SH2) domains responsible for its association with tyrosine-phosphorylated proteins. In this study, expression of dominant interfering mutants of SHPTP2 was found to inhibit insulin stimulation of c-fos reporter gene expression and activation of the 42-kDa (Erk2) and 44-kDa (Erk1) mitogen-activated protein kinases. Cotransfection of dominant interfering SHPTP2 mutants with v-Ras or Grb2 indicated that SHPTP2 regulated insulin signaling either upstream of or in parallel to Ras function. Furthermore, phosphotyrosine blotting and immunoprecipitation identified the 125-kDa focal adhesion kinase (pp125FAK) as a substrate for insulin-dependent tyrosine dephosphorylation. These data demonstrate that SHPTP2 functions as a positive regulator of insulin action and that insulin signaling results in the dephosphorylation of tyrosine-phosphorylated pp125FAK.
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PMID:Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. 753 37

In isolated rat hepatocytes angiotensin II and phorbol 12-myristate 13-acetate (PMA) induce the expression of c-fos. We studied the possible transduction pathway(s) involved in this effect using inhibitors of serine-threonine and tyrosine protein kinases. Calphostin and staurosporine, inhibitors of protein kinase C and other serine-threonine protein kinases, block in a dose-dependent manner the effect of angiotensin II and PMA. Interestingly, genistein also blocks the induction of this proto-oncogene, suggesting a role for tyrosine protein kinases. Inhibitors of serine-threonine protein phosphatases, such as okadaic acid, microcystin LR and calyculin also induce c-fos expression. These data suggest that protein phosphatases exert a tonic inhibitory control of c-fos expression. The effect of these phosphatase inhibitors were not blocked by staurosporine, calphostin or genistein. Our results suggest that the expression of c-fos in rat hepatocytes is regulated by complex phosphorylation-dephosphorylation cascade(s) probably involving serine/threonine and tyrosine protein kinase and protein phosphatase activities.
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PMID:Protein kinases and phosphatases modulate c-fos expression in rat hepatocytes. Effects of angiotensin II and phorbol myristate acetate. 753 72

Insulin stimulates the activity of mitogen-activated protein kinase (MAPK) via its upstream activator, MAPK kinase (MEK), a dual specificity kinase that phosphorylates MAPK on threonine and tyrosine. The potential role of MAPK activation in insulin action was investigated with the specific MEK inhibitor PD98059. Insulin stimulation of MAPK activity in 3T3-L1 adipocytes (2.7-fold) and L6 myotubes (1.4-fold) was completely abolished by pretreatment of cells with the MEK inhibitor, as was the phosphorylation of MAPK and pp90Rsk, and the transcriptional activation of c-fos. Insulin receptor autophosphorylation on tyrosine residues and activation of phosphatidylinositol 3'-kinase were unaffected. Pretreatment of cells with PD98059 had no effect on basal and insulin-stimulated glucose uptake, lipogenesis, and glycogen synthesis. Glycogen synthase activity in extracts from 3T3-L1 adipocytes and L6 myotubes was increased 3-fold and 1.7-fold, respectively, by insulin. Pretreatment with 10 microM PD98059 was without effect. Similarly, the 2-fold activation of protein phosphatase 1 by insulin was insensitive to PD98059. These results indicate that stimulation of the MAPK pathway by insulin is not required for many of the metabolic activities of the hormone in cultured fat and muscle cells.
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PMID:Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. 765 64

Polyomavirus middle T antigen (MT) interacts with several cellular proteins involved in cell proliferation. MT forms complexes with protein phosphatase 2A (PP2A), pp60c-src (and the related kinases c-fyn and c-yes), and phosphatidylinositol-3 kinase. We made a single point mutation in MT, changing a conserved cysteine residue at position 120 to tryptophan, and characterized the biochemical and biological properties of the mutant (C120W) protein. The mutant MT protein does not associate with PP2A, pp60c-src, or phosphatidylinositol-3 kinase as judged by coimmunoprecipitation and associated phosphatase or kinase activity. The C120W mutant is defective in activation of c-fos expression and in morphological transformation of NIH 3T3 cells.
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PMID:Mutation of a cysteine residue in polyomavirus middle T antigen abolishes interactions with protein phosphatase 2A, pp60c-src, and phosphatidylinositol-3 kinase, activation of c-fos expression, and cellular transformation. 768 Mar 88

In this study, the signal cascade transducing carbachol stimulation into c-fos expression in SH-SY5Y neuroblastoma cells was investigated. 1,2-Diacylglycerol formation and c-fos expression were mediated via stimulation of muscarinic M1 receptors and the first 5 min of receptor stimulation were critical for these events. Application of 1,2-dioctanoylglycerol induced c-fos expression and this, as well as carbachol-stimulated c-fos expression, was inhibited by protein kinase C inhibitors. Increasing the intracellular Ca2+ concentration had only small effects on c-fos expression. There was a dependency on extracellular Ca2+ for maximal c-fos expression and 1,2-diacylglycerol formation. The carbachol-stimulated c-fos expression was potentiated by application of the protein phosphatase inhibitor okadaic acid. These results demonstrate the importance of 1,2-diacylglycerol formation for muscarinic receptor-stimulated, protein kinase C-mediated c-fos expression in the SH-SY5Y cells and that this cascade is counteracted by an okadaic acid-sensitive protein phosphatase.
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PMID:Mechanisms of muscarinic receptor-stimulated expression of c-fos in SH-SY5Y cells. 792 9


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