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)

PC12 pheochromocytoma cells contain at least two different and separable kinases that phosphorylate the S6 protein of the ribosomes. The activity of one of these S6 kinases is increased by treatment of the cells with nerve growth factor and of the other by treatment with epidermal growth factor. Okadaic acid increases the activity of the nerve growth factor-sensitive S6 kinase. The data suggest that the nerve growth factor-sensitive S6 kinase is activated by phosphorylation on serine or threonine residues and is inactivated by either phosphatase 1 or phosphatase 2A, probably the latter.
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PMID:Okadaic acid stimulates the activity of the nerve growth factor-sensitive S6 kinase of PC12 cells. 164 6

Tyrosine hydroxylase, which catalyzes the initial step in catecholamine biosynthesis, is phosphorylated at serines 8, 19, 31, and 40 in intact pheochromocytoma (PC12) cells (Haycock, J.W. (1990) J. Biol. Chem. 265, 11682-11691). After 32Pi labeling of rat corpus striata in vivo or rat corpus striatal synaptosomes, 32P incorporation into tyrosine hydroxylase occurred predominantly at serines 19, 31, and 40. Electrical stimulation (30 Hz, 20 min) of the medial forebrain bundle (containing the afferent dopaminergic fibers) increased 32P incorporation into each of the three sites. Brief depolarization of the synaptosomes with elevated [K+]o (20-60 mM, 5-30 s) or veratridine (50 microM, 2 min) produced a selective increase in 32P incorporation into Ser19. Phorbol 12,13-dibutyrate (1 microM, 5 min) increased 32P incorporation into Ser31, and cAMP-acting agents such as forskolin (10 microM, 5 min) increased 32P incorporation into Ser40. In contrast, 32P incorporation into Ser8, which was usually detectable but very low, was not regulated either in vivo or in situ by any of the activators of signal transduction pathways. In synaptosomes, the only treatment found to increase Ser8 phosphorylation was okadaic acid (a protein phosphatase inhibitor), which increased 32P incorporation into all four phosphorylation sites. Thus, three different signal transduction systems appear to mediate the physiological regulation of tyrosine hydroxylase phosphorylation at three different sites.
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PMID:Tyrosine hydroxylase in rat brain dopaminergic nerve terminals. Multiple-site phosphorylation in vivo and in synaptosomes. 167 15

PC-12 pheochromocytoma cells contain a growth factor-sensitive protein kinase that phosphorylates microtubule associated protein 2 (MAP-2). This MAP kinase is also activated by the protein phosphatase inhibitor okadaic acid (OA). Additionally, OA potentiates the NGF-dependent activation of MAP kinase, but causes only a modest potentiation (20%) of the maximal activation observed with EGF. Since OA is a specific serine/threonine phosphatase inhibitor, these results suggest that serine/threonine phosphorylation may be involved in the hormonal regulation of MAP kinase.
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PMID:Okadaic acid stimulates the activity of microtubule associated protein kinase in PC-12 pheochromocytoma cells. 216 Dec 19

Protein purification and molecular cloning have defined five classes of protein serine-threonine phosphatase catalytic subunits referred to as types 1, 2A, 2B (calcineurin), 2C, and X. Protein serine-threonine phosphatases 1, 2A, 2B, and X appear to have significant sequence homologies, whereas the 2C enzyme is more divergent. We have used the polymerase chain reaction to define the multiplicity of the closely related types 1, 2A, 2B, and X phosphatase catalytic subunits in two clonal cell lines, rat PC12 pheochromocytoma and rat FTO-2B hepatoma. RNAs for all four related phosphatase types were expressed in both cell lines. In addition to the phosphatase X enzyme, four phosphatase 1, two phosphatase 2A, and three phosphatase 2B isoforms were identified in PC12 and FTO-2B cells. The results indicate a large multiplicity of protein serine-threonine phosphatases within clonal cells of different tissue origin, suggesting that their role in cell regulation will be as divergent as that for the protein serine-threonine kinases.
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PMID:Multiplicity of protein serine-threonine phosphatases in PC12 pheochromocytoma and FTO-2B hepatoma cells. 217 76

Calmodulin-dependent phosphoprotein phosphatase (CaMDP) activity has been found in each of three cultured cell lines: rat pheochromocytoma (PC12), glioma (C6), and pituitary adenoma (GH3) cells. These CaMDP activities bind to immobilized calmodulin in the presence of Ca2+ and are eluted by EGTA. Sucrose density centrifugation revealed that the phosphatase activities exhibited sedimentation coefficients of 4.37, 4.23, and 4.59 for proteins derived from C6, GH3, and PC12 cells, respectively. The Stokes radii measured for the PC12 and C6 activities were 41.8 and 40.0 A, respectively. The estimated molecular weights calculated for the enzymes from these data are 79,100 and 72,200. The phosphatase activities required the presence of divalent cations such as Ca2+ or Mn2+ for expression of activity, which was optimal only in the presence of calmodulin. The apparent Km for phosphorylated myelin basic protein substrate was 8 microM. Affinity-purified antibodies to the B subunit of bovine brain CaMDP were found by immunoblot (Western blot) to cross-react with a single protein among proteins extracted from PC12, C6, and GH3 cells that had been resolved by two-dimensional electrophoresis. In each case, the cross-reacting protein exhibited an Mr of 16,000 and an isoelectric point of 4.7, values virtually identical to those reported previously for the B subunit of bovine brain CaMDP (sometimes called calcineurin). This cross-reacting protein was found among cellular proteins eluted from immobilized calmodulin by EGTA. Immunocytochemical localization of the cross-reacting protein in undifferentiated PC12 cells or in cells differentiated in response to nerve growth factor revealed its presence diffusely throughout the cytoplasm. These experiments support the contention that each of these cell lines contains a calmodulin-regulated phosphatase homologous physically and kinetically, and immunologically related to bovine brain CaMDP.
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PMID:Calmodulin-dependent phosphatases of PC12, GH3, and C6 cells: physical, kinetic, and immunochemical properties. 329 45

The immunosuppressant drug FK506 acts by binding to receptor proteins, FK506-binding proteins (FKBPs), which in turn can bind to and regulate a Ca(2+)-dependent phosphatase, calcineurin, and a Ca2+ release channel, the ryanodine receptor. Based on our findings in regeneration models that levels of FKBPs during neural regeneration parallel those of growth-associated protein GAP43, a calcineurin substrate that regulates neurite extension, we examined effects of FK506 in PC12 rat pheochromocytoma cells and in rat sensory ganglia. FK506 enhances neurite outgrowth in both systems by increasing sensitivity to nerve growth factor. Blockade of FK506 actions in sensory ganglia by rapamycin, an FK506 antagonist, establishes that these effects involve FKBPs. Rapamycin itself stimulates neurite outgrowth in PC12 cells. These drug effects are detected at subnanomolar concentrations, suggesting therapeutic application in diseases involving neural degeneration.
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PMID:Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. 751 27

The serine/threonine protein phosphatase inhibitor okadaic acid (OA) was found to enhance mRNA transcripts of c-fos and of the jun family of proto-oncogenes including c-jun, jun B and jun D in cultured pheochromocytoma PC12 cells. This expression remained elevated for more than 8 hr. An increase in the binding of the transcription factor activator protein 1 (AP1) to its DNA consensus sequence that occurred prior to early gene transcription was observed. Enhanced AP1 activity was still observed when OA was added to the cells together with the transcription inhibitor actinomycin D, or with the protein synthesis inhibitor cycloheximide, indicating that it is actually AP1 activation due to posttranslational modifications that triggers transcription of the fos and jun genes. AP1 was activated through serine/threonine phosphorylation since its activation was abolished when nuclear extracts of OA-treated cells were incubated with protein phosphatase-1 or, to a lesser extent, with protein phosphatase-2A. C-Jun and Jun D proteins are likely candidates for being phosphorylated, since they were shown to constitute the AP1 complex at the time when it was activated (2 hr after OA addition).
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PMID:Okadaic acid induces activator protein 1 activity and immediate early gene transcription in rat pheochromocytoma cells. Mechanism of action. 808 Apr 55

Components of a protein tyrosine phosphorylation/dephosphorylation network were identified in the cyanobacterium Anabaena sp. strain PCC 7120. Three phosphotyrosine (P-Tyr) proteins of 27, 36, and 52 kDa were identified through their conspicuous immunoreactions with RC20H monoclonal antibodies specific for P-Tyr. These immunoreactions were outcompeted completely by free P-Tyr (5 mM) but not by phosphoserine or phosphothreonine. The P-Tyr content of the three major P-Tyr proteins and several minor proteins increased with their time of incubation in the presence of Mg-ATP and the protein phosphatase inhibitors sodium orthovanadate and sodium fluoride. Incubation of the same extracts with [gamma-32P]ATP but not [alpha-32P]ATP led to the phosphorylation of five polypeptides with molecular masses of 20, 27, 52, 85, and 100 kDa. Human placental protein tyrosine phosphatase 1B, with absolute specificity for P-Tyr, liberated significant quantities of 32Pi from four of the polypeptides, confirming that a portion of the protein-bound phosphate was present as 32P-Tyr. Alkaline phosphatase and the dual-specificity protein phosphatase IphP from the cyanobacterium Nostoc commune UTEX 584 also dephosphorylated these proteins and did so with greater apparent efficiency. Two of the polypeptides were partially purified, and phosphoamino analysis identified 32P-Tyr, [32P]phosphoserine, and [32P]phosphothreonine. Anabaena sp. strain PCC 7120 cell extracts contained a protein tyrosine phosphatase activity that was abolished in the presence of sodium orthovanadate and inhibited significantly by the sulfhydryl-modifying agents p-hydroxymercuriphenylsulfonic acid and p-hydroxymercuribenzoate as well as by heparin. In Anabaena sp. strain PCC 7120 the presence and/or phosphorylation status of P-Tyr proteins was influenced by incident photon flux density.
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PMID:Protein tyrosine phosphorylation in the cyanobacterium Anabaena sp. strain PCC 7120. 907 18

The kinetics and biochemical effects of microcystins in rainbow trout were studied with freeze-dried toxic cells of Microcystis aeruginosa, strain PCC 7806. Following in vivo exposure the changes in liver histology were observed over a 72 hr period and the absorption of microcystins from the gastrointestinal tract into the blood and liver, as well as the inhibition of hepatic protein phosphatase 1 and 2A activities, were recorded using the protein phosphatase inhibition assay. The interaction between microcystins and trout liver phosphatases was further tested in vitro using the protein phosphatase inhibition assay. The in vivo experiments demonstrated a high organotropy of microcystins for the liver, where rapid and total inhibition of protein phosphatase 1 and 2A activity was observed. Maximal inhibition of phosphatases was observed 3 hr after gavage. At that time-point, approximately 63% of the toxin present in the liver was refractive to detection via the phosphatase inhibition assay and therefore most likely covalently bound to cellular proteins. The inhibition of hepatic protein phosphatases 1 and 2A proved to be transient only, as a progressive increase in phosphatase activity was observed beginning 12 hr after gavage of the fish, reaching approximately 50% of the control activity at 72 hr. In contrast, liver damage continued to progress despite this renewed protein phosphatase activity.
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PMID:Biochemical characterization of microcystin toxicity in rainbow trout (Oncorhynchus mykiss). 913 13

Several bloom-forming cyanobacterial genera produce potent inhibitors of eukaryotic protein phosphatases called microcystins. Microcystins are hepatotoxic cyclic heptapeptides and are presumed to be synthesized non-ribosomally by peptide synthetases. We identified putative peptide synthetase genes in the microcystin-producing strain Microcystis aeruginosa PCC 7806. Non-hepatotoxic strains of M. aeruginosa lack these genes. Strain PCC 7806 was transformed to chloramphenicol resistance. The antibiotic resistance cassette insertionally inactivated a peptide synthetase gene of strain PCC 7806 as revealed by Southern hybridization and DNA amplification. This is the first report of genetic transformation and mutation, by homologous recombination, of a bloom-forming cyanobacterium. Chemical and enzymatic analyses, including high-performance liquid chromatography (HPLC), mass spectrometry, amino acid activation, and protein phosphatase inhibition, revealed the inability of derived mutant cells to produce any variant of microcystin while maintaining their ability to synthesize other small peptides. The disrupted gene therefore encodes a peptide synthetase (microcystin synthetase) that is specifically involved in the biosynthesis of microcystins. Our results confirm that microcystins are synthesized non-ribosomally and that a basic difference between toxic and non-toxic strains of M. aeruginosa is the presence of one or more genes coding for microcystin synthetases.
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PMID:Insertional mutagenesis of a peptide synthetase gene that is responsible for hepatotoxin production in the cyanobacterium Microcystis aeruginosa PCC 7806. 942 7


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