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Results: 11 to 16 of 16

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The mechanism of action of cantharidin in smooth muscle.
Knapp J, Bokník P, Huke S, Lüss H, Müller FU, Müller T, Nacke P, Schmitz W, Vahlensieck U, Neumann J
(1998) Br J Pharmacol 123: 911-9
MeSH Terms: Animals, Blotting, Northern, Calcium, Cantharidin, Catalysis, Cattle, Cells, Cultured, Cytosol, Enzyme Inhibitors, In Vitro Techniques, Muscle Contraction, Muscle, Smooth, Vascular, Okadaic Acid, Phosphoprotein Phosphatases, Phosphorylation
Show Abstract · Added May 27, 2014
1. The aim of this study was to investigate the mechanism(s) of the vasoconstrictor effect of cantharidin in bovine preparations. 2. Catalytic subunits of protein phosphatase type 1 (PP 1) and type 2A (PP 2A) were immunologically identified in coronary arteries, isolated smooth muscle cells and ventricular myocardium. 3. The mRNAs coding for catalytic subunits of PP 1alpha, PP 1beta and PP 2Aalpha were identified by hybridization with specific cDNA-probes in total RNA from coronary arteries, isolated smooth muscle cells and ventricles. 4. The activities of catalytic subunits of PP 1 and PP 2A separated by column chromatography from coronary arteries, isolated smooth muscle cells and ventricles were inhibited by cantharidin in a concentration-dependent manner. 5. Cantharidin increased the phosphorylation state of smooth muscle proteins including the regulatory light chains of myosin in 32P-labelled intact smooth muscle cells in a concentration-dependent manner. 6. Cantharidin did not affect cytosolic calcium concentrations in aortic smooth muscle cells. 7. It is suggested that cantharidin contracts smooth muscle preparations by increasing the phosphorylation state of regulatory proteins due to inhibition of phosphatase activities. Thus, cantharidin might be a useful tool to study the function of phosphatases in smooth muscle.
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15 MeSH Terms
Phosphorylation and regulation of antidepressant-sensitive serotonin transporters.
Ramamoorthy S, Giovanetti E, Qian Y, Blakely RD
(1998) J Biol Chem 273: 2458-66
MeSH Terms: Carrier Proteins, Cell Line, Cell Membrane, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Enzyme Inhibitors, Humans, Membrane Glycoproteins, Membrane Transport Proteins, Molecular Weight, Nerve Tissue Proteins, Okadaic Acid, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinase C, Second Messenger Systems, Serotonin, Serotonin Plasma Membrane Transport Proteins, Stereoisomerism, Tetradecanoylphorbol Acetate
Show Abstract · Added July 10, 2013
Antidepressant-sensitive serotonin (5-hydroxytryptamine, 5HT) transporters (SERTs) are responsible for efficient synaptic clearance of extracellular 5HT. Previously (Qian, Y., Galli, A., Ramamoorthy, S., Risso, S., DeFelice, L. J., and Blakely, R. D. (1997) J. Neurosci. 17, 45-47), we demonstrated that protein kinase (PKC)-linked pathways in transfected HEK-293 cells lead to the internalization of cell-surface human (h) SERT protein and a reduction in 5HT uptake capacity. In the present study, we report that PKC activators rapidly, and in a concentration-dependent manner, elevate the basal level of hSERT phosphorylation 5-6-fold. Similarly, protein phosphatase (PP1/PP2A) inhibitors down-regulate 5HT transport and significantly elevate hSERT 32P incorporation, effects that are additive with those of PKC activators. Moreover, hSERT phosphorylation induced by beta-phorbol 12-myristate 13-acetate is abolished selectively by the PKC inhibitors staurosporine and bisindolylmaleimide I, whereas hSERT phosphorylation induced by phosphatase inhibitors is insensitive to these agents at comparable concentrations. Protein kinase A and protein kinase G activators fail to acutely down-regulate 5HT uptake but significantly enhance hSERT phosphorylation. Basal hSERT and okadaic acid-induced phosphorylation were insensitive to chelation of intracellular calcium and Ca2+/calmodulin-dependent protein kinase inhibitors. Together these results reveal hSERT to be a phosphoprotein whose phosphorylation state is likely to be tightly controlled by multiple kinase and phosphatase pathways that may also influence the transporter's regulated trafficking.
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20 MeSH Terms
Expression of glutathione and gamma-glutamylcysteine synthetase mRNA is Jun dependent.
Sekhar KR, Meredith MJ, Kerr LD, Soltaninassab SR, Spitz DR, Xu ZQ, Freeman ML
(1997) Biochem Biophys Res Commun 234: 588-93
MeSH Terms: Animals, Gene Expression Regulation, Glutamate-Cysteine Ligase, Glutathione, Humans, Mice, Okadaic Acid, Proto-Oncogene Proteins c-jun, RNA, Messenger, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
The gene GLCLC encodes the catalytic subunit of gamma-glutamylcysteine synthetase (glutamate-cysteine ligase E.C. 6.3.2.2), the rate limiting enzyme for glutathione synthesis. When HepG2 cells were exposed to the serine/threonine phosphatase inhibitor okadaic acid (OA), increased expression of GLCLC was observed, as was the development of resistance to xenobiotic induced GSH depletion. Okadaic acid is known to activate both NF-kappaB and AP-1 activity. Inhibition of NF-kappaB activity by overexpression of an IkappaB alpha transdominant inhibitor or exposure to the protease inhibitor TLCK did not inhibit the OA mediated increase in GLCLC transcripts. Fibroblasts derived from a mouse containing a c-Jun null mutation exhibited diminished AP-1 binding activity, reduced levels of GLCLC message, and a correspondingly low GSH concentration compared to wild type cells. When the null cells, which express Jun B and Jun D, were exposed to OA, AP-1 binding activity increased, as did expression of GLCLC message. These results indicate that AP-1 transcription factors participate in the regulation of glutathione metabolism.
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10 MeSH Terms
Novel phosphorylation sites of eukaryotic initiation factor-4F and evidence that phosphorylation stabilizes interactions of the p25 and p220 subunits.
Bu X, Haas DW, Hagedorn CH
(1993) J Biol Chem 268: 4975-8
MeSH Terms: Cells, Cultured, Ethers, Cyclic, Eukaryotic Initiation Factor-4F, Okadaic Acid, Peptide Initiation Factors, Phosphorylation, RNA, Messenger
Show Abstract · Added March 13, 2015
Only serine phosphorylation of eukaryotic initiation factor-4E (eIF-4E) has been previously reported in intact cells. We found that treatment of HepG2 cells with okadaic acid resulted in as much as 20% of eukaryotic initiation factor (eIF)-4E phosphorylation occurring on threonine residues and that tryptic phosphopeptide maps showed several previously unrecognized phosphopeptides. Analysis of p220 from control and okadaic acid-treated cells demonstrated serine and threonine phosphorylation under both conditions. However, a unique pattern of phosphopeptides in okadaic acid-treated cells was observed. The most notable finding was that hyperphosphorylation of eIF-4E and p220 increased binding of p220 but not eIF-4E to the m7GTP cap structure. We suggest that phosphorylation of eIF-4E is more complicated than previously recognized and that hyperphosphorylation of eIF-4E and p220 recruits more p220 into the protein complex that associates with mRNA caps. A better understanding of these protein-protein and protein-mRNA interactions may aid the design of anti-sense directed chemistries that disrupt such interactions for a specific target mRNA (Baker, B.F., Miraglia, L., and Hagedorn, C. H. (1992) J. Biol. Chem. 267, 11495-11499).
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7 MeSH Terms
Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation.
Wadzinski BE, Wheat WH, Jaspers S, Peruski LF, Lickteig RL, Johnson GL, Klemm DJ
(1993) Mol Cell Biol 13: 2822-34
MeSH Terms: Amino Acid Sequence, Base Sequence, Bucladesine, Carcinoma, Hepatocellular, Cell Nucleus, Cloning, Molecular, Cyclic AMP Response Element-Binding Protein, Ethers, Cyclic, Female, Gene Expression Regulation, Neoplastic, Humans, Kinetics, Leukemia, Promyelocytic, Acute, Liver Neoplasms, Macromolecular Substances, Molecular Sequence Data, Okadaic Acid, Oligodeoxyribonucleotides, Phosphoenolpyruvate Carboxykinase (GTP), Phosphoprotein Phosphatases, Phosphorylation, Placenta, Polymerase Chain Reaction, Pregnancy, Promoter Regions, Genetic, Protein Kinases, Protein Phosphatase 2, Recombinant Proteins, Transcription, Genetic, Tumor Cells, Cultured
Show Abstract · Added December 10, 2013
Cyclic AMP (cAMP)-dependent protein kinase A (PKA) stimulates the transcription of many eucaryotic genes by catalyzing the phosphorylation of the cAMP-regulatory element binding protein (CREB). Conversely, the attenuation or inhibition of cAMP-stimulated gene transcription would require the dephosphorylation of CREB by a nuclear protein phosphatase. In HepG2 cells treated with the protein serine/threonine (Ser/Thr) phosphatase inhibitor okadaic acid, dibutyryl-cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) promoter was enhanced over the level of PEPCK gene transcription observed in cells treated with dibutyryl-cAMP alone. This process was mediated, at least in part, by a region of the PEPCK promoter that binds CREB. Likewise, okadaic acid prevents the dephosphorylation of PKA-phosphorylated CREB in rat liver nuclear extracts and enhances the ability of PKA to stimulate transcription from the PEPCK promoter in cell-free reactions. The ability of okadaic acid to enhance PKA-stimulated transcription in vitro was entirely dependent on the presence of CREB in the reactions. The phospho-CREB (P-CREB) phosphatase activity present in nuclear extracts coelutes with protein Ser/Thr phosphatase type 2A (PP2A) on Mono Q, amino-hexyl Sepharose, and heparin agarose columns and was chromatographically resolved from nuclear protein Ser/Thr-phosphatase type 1 (PP1). Furthermore, P-CREB phosphatase activity in nuclear extracts was unaffected by the heat-stable protein inhibitor-2, which is a potent and selective inhibitor of PP1. Nuclear PP2A dephosphorylated P-CREB 30-fold more efficiently than did nuclear PP1. Finally, when PKA-phosphorylated CREB was treated with immunopurified PP2A and PP1, the PP2A-treated CREB did not stimulate transcription from the PEPCK promoter in vitro, whereas the PP1-treated CREB retained the ability to stimulate transcription. Nuclear PP2A appears to be the primary phosphatase that dephosphorylates PKA-phosphorylated CREB.
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30 MeSH Terms
Transforming growth factor alpha regulation of two zinc finger-containing immediate early response genes in intestine.
DuBois RN, Bishop PR, Graves-Deal R, Coffey RJ
(1995) Cell Growth Differ 6: 523-9
MeSH Terms: Animals, Base Sequence, Blotting, Northern, Carcinogens, Cell Division, Cells, Cultured, DNA-Binding Proteins, Early Growth Response Protein 1, Epithelium, Ethers, Cyclic, Gene Expression Regulation, Immediate-Early Proteins, In Situ Hybridization, Intestinal Mucosa, Male, Molecular Sequence Data, Okadaic Acid, Protein Biosynthesis, Proteins, RNA, Messenger, Rats, Tetradecanoylphorbol Acetate, Transcription Factors, Transcription, Genetic, Transforming Growth Factor alpha, Tristetraprolin, Zinc Fingers
Show Abstract · Added March 27, 2014
The epithelium lining the intestine undergoes rapid and continuous renewal. Growth factors play a role in intestinal epithelial growth regulation in vitro and in vivo. In this study, transforming growth factor alpha (TGF alpha) is shown to act as a mitogen and induce the expression of two zinc finger-containing immediate early genes [Zif268 (zinc finger protein 268) and Nup475 (nuclear protein 475)] in rat intestinal epithelial (RIE-1) cells in culture. These two gene products were initially isolated from serum-treated fibroblasts and represent growth-stimulated transcription factors. In TGF alpha-treated RIE-1 cells, nuclear run-on experiments demonstrate that TGF alpha induction of these two genes is regulated predominantly at the level of gene transcription. Utilizing in situ hybridization techniques, we show that systemic administration of TGF alpha induces expression of these two genes in the rat intestine. The predominant expression of zif268 is observed in the proliferative crypt compartment, whereas nup475 expression is concentrated in the postmitotic luminal compartment. These studies demonstrate that two immediate early genes, Nup475 and Zif268, are induced in intestinal epithelium in vitro and in vivo and thus may play a role in intestinal epithelial growth and/or differentiation.
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27 MeSH Terms