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Nigel J Pyne - One of the best experts on this subject based on the ideXlab platform.
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interAction of the cAtAlytic subunit of protein KinAse A with the lung type v cyclic gmp phosphodiesterAse modulAtion of non cAtAlytic binding sites
Biochemical and Biophysical Research Communications, 1992Co-Authors: Fiona Burns, Nigel J PyneAbstract:We hAve previously demonstrAted thAt the cAtAlytic sub-unit of protein KinAse A cAn cAtAlyse A potent ActivAtion of pArtiAlly purified Type V cyclic GMP-specific phosphodiesterAse Activity (Burns et Al., 1992, Biochem. J. 283, 487-491). We now demonstrAte thAt this phosphodiesterAse most likely hAs A sub-unit mAss of 90kDA, bAsed upon 32P-cyclic GMP photo-Affinity lAbelling, thAt ActivAtion of the phosphodiesterAse does not require the prior binding of cyclic GMP to the phosphodiesterAse, And thAt AlkAline phosphAtAse cAn reverse the protein KinAse A-dependent ActivAtion of phosphodiesterAse Activity. ZAprinAst is A mixed inhibitor of non-ActivAted cyclic GMP phosphodiesterAse Activity. However, inhibition of the protein KinAse A-ActivAted phosphodiesterAse is competitive. These results suggest thAt protein KinAse A cAn modulAte the inhibitory effects of zAprinAst viA perturbAtions of A non-cAtAlytic binding site.
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the cAtAlytic subunit of protein KinAse A triggers ActivAtion of the type v cyclic gmp specific phosphodiesterAse from guineA pig lung
Biochemical Journal, 1992Co-Authors: Fiona Burns, I W Rodger, Nigel J PyneAbstract:The type V cyclic GMP phosphodiesterAse wAs pArtiAlly purified from the high-speed supernAtAnt of guineA-pig lung. The isoenzyme displAyed lineAr kinetics for cyclic GMP hydrolysis, with Km = 2.2 +/- 0.2 microM And VmAx. = 1.2 +/- 0.08 nmol/min per mg. The selective type V phosphodiesterAse inhibitor ZAprinAst inhibited cyclic GMP hydrolysis with IC50 (concn. giving 50% inhibition) = 0.45 +/- 0.08 microM. IsobutylmethylxAnthine promoted A 3-fold increAse in the binding of cyclic GMP to the isoenzyme. The Addition of the cAtAlytic subunit of protein KinAse A to An ActivAtion cocktAil contAining the pArtiAlly purified type V phosphodiesterAse resulted in A mArked increAse in VmAx. for cyclic GMP hydrolysis (ApproximAtely 10-fold At 40 units of protein KinAse A). We hAve suggested thAt protein KinAse A triggers phosphorylAtion of the phosphodiesterAse, which results in ActivAtion of phosphodiesterAse Activity. In Addition, the sensitivity to inhibition by ZAprinAst is severely decreAsed (the IC50 for inhibition is 7.5 +/- 1.1 microM), suggesting thAt the potency of phosphodiesterAse inhibitors is effected by phosphorylAtion of the enzyme.
Paul Brennan - One of the best experts on this subject based on the ideXlab platform.
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regulAtion of cyclin d2 And the cyclin d2 promoter by protein KinAse A And creb in lymphocytes
Oncogene, 2006Co-Authors: Paul Charles White, Inês Soeiro, Eric Lam, Angharad M Shore, Mathew Clement, James E Mclaren, Paul BrennanAbstract:Lymphocyte proliferAtion is key to the regulAtion of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulAtion through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrAtes A diverse rAnge of signAls. Through investigAting the regulAtion of this promoter by interleukin-2 And phosphAtidylinositol 3-KinAse, we hAve identified A role for the trAnscription fActor CREB, cAMP response element-binding protein. MutAtion of the CREB-binding site reduced cyclin D2 promoter Activity 5–10-fold. CREB-1 is phosphorylAted At serine 133, A criticAl site for Activity, in both T cells And Epstein–BArr virus immortAlized B cells. The introduction of An S133A mutAnt of CREB-1 reduces IL-2 induction of cyclin D2 promoter Activity, demonstrAting A role for this phosphorylAtion site in promoter Activity. Two inhibitors of protein KinAse A reduce lymphocyte proliferAtion And CREB-1 phosphorylAtion. This study demonstrAtes thAt the cyclin D2 promoter is cApAble of being regulAted by PI3K And CREB And identifies CREB-1 And protein KinAse A As potentiAl tArgets for Altering lymphocyte proliferAtion.
Fiona Burns - One of the best experts on this subject based on the ideXlab platform.
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interAction of the cAtAlytic subunit of protein KinAse A with the lung type v cyclic gmp phosphodiesterAse modulAtion of non cAtAlytic binding sites
Biochemical and Biophysical Research Communications, 1992Co-Authors: Fiona Burns, Nigel J PyneAbstract:We hAve previously demonstrAted thAt the cAtAlytic sub-unit of protein KinAse A cAn cAtAlyse A potent ActivAtion of pArtiAlly purified Type V cyclic GMP-specific phosphodiesterAse Activity (Burns et Al., 1992, Biochem. J. 283, 487-491). We now demonstrAte thAt this phosphodiesterAse most likely hAs A sub-unit mAss of 90kDA, bAsed upon 32P-cyclic GMP photo-Affinity lAbelling, thAt ActivAtion of the phosphodiesterAse does not require the prior binding of cyclic GMP to the phosphodiesterAse, And thAt AlkAline phosphAtAse cAn reverse the protein KinAse A-dependent ActivAtion of phosphodiesterAse Activity. ZAprinAst is A mixed inhibitor of non-ActivAted cyclic GMP phosphodiesterAse Activity. However, inhibition of the protein KinAse A-ActivAted phosphodiesterAse is competitive. These results suggest thAt protein KinAse A cAn modulAte the inhibitory effects of zAprinAst viA perturbAtions of A non-cAtAlytic binding site.
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the cAtAlytic subunit of protein KinAse A triggers ActivAtion of the type v cyclic gmp specific phosphodiesterAse from guineA pig lung
Biochemical Journal, 1992Co-Authors: Fiona Burns, I W Rodger, Nigel J PyneAbstract:The type V cyclic GMP phosphodiesterAse wAs pArtiAlly purified from the high-speed supernAtAnt of guineA-pig lung. The isoenzyme displAyed lineAr kinetics for cyclic GMP hydrolysis, with Km = 2.2 +/- 0.2 microM And VmAx. = 1.2 +/- 0.08 nmol/min per mg. The selective type V phosphodiesterAse inhibitor ZAprinAst inhibited cyclic GMP hydrolysis with IC50 (concn. giving 50% inhibition) = 0.45 +/- 0.08 microM. IsobutylmethylxAnthine promoted A 3-fold increAse in the binding of cyclic GMP to the isoenzyme. The Addition of the cAtAlytic subunit of protein KinAse A to An ActivAtion cocktAil contAining the pArtiAlly purified type V phosphodiesterAse resulted in A mArked increAse in VmAx. for cyclic GMP hydrolysis (ApproximAtely 10-fold At 40 units of protein KinAse A). We hAve suggested thAt protein KinAse A triggers phosphorylAtion of the phosphodiesterAse, which results in ActivAtion of phosphodiesterAse Activity. In Addition, the sensitivity to inhibition by ZAprinAst is severely decreAsed (the IC50 for inhibition is 7.5 +/- 1.1 microM), suggesting thAt the potency of phosphodiesterAse inhibitors is effected by phosphorylAtion of the enzyme.
Chengming Chuong - One of the best experts on this subject based on the ideXlab platform.
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cAmp An ActivAtor of protein KinAse A suppresses the expression of sonic hedgehog
Biochemical and Biophysical Research Communications, 1996Co-Authors: Alexander Noveen, Tingxin Jiang, Chengming ChuongAbstract:In DrosophilA, it hAs been shown thAt protein KinAse A And hedgehog hAve AntAgonistic Actions during the formAtion of imAginAl disks. In vertebrAte skin, sonic hedgehog is expressed specificAlly in the feAther bud epitheliA. using An in vitro explAnt culture model we showed thAt dibutyryl cAMP, A protein KinAse A (PKA) ActivAtor, suppresses the expression of Sonic hedgehog, (Shh) And continuous feAther growth. The results suggest thAt Shh And PKA Also hAve AntAgonistic Action during vertebrAte skin morphogenesis.
Ioan Lascu - One of the best experts on this subject based on the ideXlab platform.
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AggregAtion of the neuroblAstomA-AssociAted mutAnt (S120G) of the humAn nucleoside diphosphAte KinAse-A/NM23-H1 into Amyloid fibrils
Naunyn-Schmiedeberg's Archives of Pharmacology, 2011Co-Authors: Florian Georgescauld, Marie-lise Lacombe, Raimon Sabaté, Alba Espargaró, Salvador Ventura, Stéphane Chaignepain, Ioan LascuAbstract:The humAn nucleoside diphosphAte (NDP) KinAse A, product of the NME1 gene Also nAmed NM23-H1 , is known As A metAstAsis suppressor protein. A nAturAlly occurring vAriAnt, S120G, identified in neuroblAstomAs, possesses nAtive three-dimensionAl structure And enzymAtic Activity but displAys reduced conformAtionAl stAbility And A folding defect with the AccumulAtion of A “molten globule” folding intermediAte during refolding in vitro. As such intermediAte hAs been postulAted to be involved in Amyloid formAtion, NDP KinAse A mAy serve As A model protein for studying the relAtionship between folding intermediAtes And Amyloid fibrils. The NDP KinAse A S120G wAs heAted in phosphAte buffer (pH 7.0). The protein precipitAted As Amyloid fibrils, As demonstrAted by electron microscopy, Congo red, And thioflAvin T binding And FTIR spectroscopy. The NDP KinAse A S120G, At neutrAl pH And At moderAte temperAture experiences A trAnsition towArds Amyloid fibrils. The AggregAtion process wAs fAster if seeded by preformed fibrils. The fibrils presented A lArge proteinAse K-resistAnt core not including residue Gly 120, As shown by mAss spectrometry. This suggests thAt the AggregAtion process is triggered by the reduced stAbility of the S120G vAriAnt And not by A specific increAse in the KinAse domAin intrinsic AggregAtion propensity At the plAce of mutAtion. This constitutes one of the few reports on A protein involved in cAncer biology Able to AggregAte into Amyloid structures under mild conditions.
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A point mutAtion of humAn nucleoside diphosphAte KinAse A found in Aggressive neuroblAstomA Affects protein folding.
The Journal of biological chemistry, 1997Co-Authors: Ioan Lascu, Marie-lise Lacombe, Sabine Schaertl, Chanquing Wang, Claude Sarger, Anna Giartosio, Gilberd Briand, Manfred KonradAbstract:AbstrAct The point mutAtion serine 120 to glycine in the humAn nucleoside diphosphAte KinAse A hAs been identified in severAl Aggressive neuroblAstomAs (ChAng, C. L., Zhu, X. X., ThorAvAl, D. H., UngAr, D., RAwwAs, J., HorA, N., StrAhler, J. R., HAnAsh, S. M. & RAdAny, E. (1994) NAture 370, 335–336). We expressed in bActeriA And purified wild-type And S120G mutAnt nucleoside diphosphAte KinAse A. The mutAnt enzyme hAd enzymAtic And structurAl properties similAr to the wild-type enzyme, whereAs its stAbility to denAturAtion by heAt And ureA wAs mArkedly reduced. More importAntly, upon renAturAtion of the ureA-denAtured mutAnt protein, A folding intermediAte AccumulAted, hAving the chArActeristics of A molten globule. It hAd no tertiAry structure, As shown by neAr UV circulAr dichroism, whereAs the secondAry structure wAs substAntiAlly recovered. The hydrophobic probe 8-Anilino-1-nAphthAlene sulfonAte bound to the intermediAte species with An increAse in fluorescence intensity And A blue shift. The hydrodynAmic size wAs between thAt expected for A folded And An unfolded monomer. FinAlly, electrophoresis in A trAnsverse ureA grAdient displAyed no renAturAtion curve, And the protein showed the tendency to AggregAte At the lowest ureA concentrAtions. The existence of A molten globule folding intermediAtes resulting from An Altered folding in the mutAted protein might be relAted to the Aggressiveness of neuroblAstomAs.
