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Science 24 July 1998:
Vol. 281. no. 5376, pp. 562 - 565
DOI: 10.1126/science.281.5376.562
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Reports

A Viral Mechanism for Inhibition of the Cellular Phosphatase Calcineurin

James E. Miskin, Charles C. Abrams, Lynnette C. Goatley, Linda K. Dixon *

The transcription factor NFAT (nuclear factor of activated T cells) controls the expression of many immunomodulatory proteins. African swine fever virus inhibits proinflammatory cytokine expression in infected macrophages, and a viral protein A238L was found to display the activity of the immunosuppressive drug cyclosporin A by inhibiting NFAT-regulated gene transcription in vivo. This it does by binding the catalytic subunit of calcineurin and inhibiting calcineurin phosphatase activity.

Institute for Animal Health, Pirbright Laboratory, Pirbright, Surrey, GU24 0NF, UK. E-mail: linda.dixon{at}bbsrc.ac.uk
*   To whom correspondence should be addressed.

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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A. G. Granja, E. G. Sanchez, P. Sabina, M. Fresno, and Y. Revilla (2009)
J. Virol. 83, 969-980
   Abstract »    Full Text »    PDF »
A238L Inhibits NF-ATc2, NF-{kappa}B, and c-Jun Activation through a Novel Mechanism Involving Protein Kinase C-{theta}-Mediated Up-Regulation of the Amino-Terminal Transactivation Domain of p300.
A. G. Granja, N. D. Perkins, and Y. Revilla (2008)
J. Immunol. 180, 2429-2442
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Comparison of the genome sequences of non-pathogenic and pathogenic African swine fever virus isolates.
D. A. G. Chapman, V. Tcherepanov, C. Upton, and L. K. Dixon (2008)
J. Gen. Virol. 89, 397-408
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The MyD116 African Swine Fever Virus Homologue Interacts with the Catalytic Subunit of Protein Phosphatase 1 and Activates Its Phosphatase Activity.
J. Rivera, C. Abrams, B. Hernaez, A. Alcazar, J. M. Escribano, L. Dixon, and C. Alonso (2007)
J. Virol. 81, 2923-2929
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African swine fever virus A238L inhibitor of NF-{kappa}B and of calcineurin phosphatase is imported actively into the nucleus and exported by a CRM1-mediated pathway.
R. N. Silk, G. C. Bowick, C. C. Abrams, and L. K. Dixon (2007)
J. Gen. Virol. 88, 411-419
   Abstract »    Full Text »    PDF »
African Swine Fever Virus Causes Microtubule-Dependent Dispersal of the trans-Golgi Network and Slows Delivery of Membrane Protein to the Plasma Membrane.
C. L. Netherton, M.-C. McCrossan, M. Denyer, S. Ponnambalam, J. Armstrong, H.-H. Takamatsu, and T. E. Wileman (2006)
J. Virol. 80, 11385-11392
   Abstract »    Full Text »    PDF »
Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L-Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation..
A. G. Granja, P. Sabina, M. L. Salas, M. Fresno, and Y. Revilla (2006)
J. Virol. 80, 10487-10496
   Abstract »    Full Text »    PDF »
Macrophage Transcriptional Responses following In Vitro Infection with a Highly Virulent African Swine Fever Virus Isolate..
F. Zhang, P. Hopwood, C. C. Abrams, A. Downing, F. Murray, R. Talbot, A. Archibald, S. Lowden, and L. K. Dixon (2006)
J. Virol. 80, 10514-10521
   Abstract »    Full Text »    PDF »
The Viral Protein A238L Inhibits TNF-{alpha} Expression through a CBP/p300 Transcriptional Coactivators Pathway.
A. G. Granja, M. L. Nogal, C. Hurtado, C. del Aguila, A. L. Carrascosa, M. L. Salas, M. Fresno, and Y. Revilla (2006)
J. Immunol. 176, 451-462
   Abstract »    Full Text »    PDF »
The Viral Protein A238L Inhibits Cyclooxygenase-2 Expression through a Nuclear Factor of Activated T Cell-dependent Transactivation Pathway.
A. G. Granja, M. L. Nogal, C. Hurtado, V. Vila, A. L. Carrascosa, M. L. Salas, M. Fresno, and Y. Revilla (2004)
J. Biol. Chem. 279, 53736-53746
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A. G. Granja, M. L. Nogal, C. Hurtado, J. Salas, M. L. Salas, A. L. Carrascosa, and Y. Revilla (2004)
J. Virol. 78, 7165-7174
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S. M. Laidlaw and M. A. Skinner (2004)
J. Gen. Virol. 85, 305-322
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The CD2v protein of African swine fever virus interacts with the actin-binding adaptor protein SH3P7.
P. C. Kay-Jackson, L. C. Goatley, L. Cox, J. E. Miskin, R. M. E. Parkhouse, J. Wienands, and L. K. Dixon (2004)
J. Gen. Virol. 85, 119-130
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Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP.
C. Zhu, K. Rao, H. Xiong, K. Gagnidze, F. Li, C. Horvath, and S. Plevy (2003)
J. Biol. Chem. 278, 39372-39382
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Murine Cytomegalovirus Infection Inhibits Tumor Necrosis Factor Alpha Responses in Primary Macrophages.
D. L. Popkin and H. W. Virgin IV (2003)
J. Virol. 77, 10125-10130
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A Conserved Calcineurin-binding Motif in Human T Lymphotropic Virus Type 1 p12I Functions to Modulate Nuclear Factor of Activated T Cell Activation.
S.-j. Kim, W. Ding, B. Albrecht, P. L. Green, and M. D. Lairmore (2003)
J. Biol. Chem. 278, 15550-15557
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The African Swine Fever Virus Protein j4R Binds to the Alpha Chain of Nascent Polypeptide-Associated Complex.
L. C. Goatley, S. R. F. Twigg, J. E. Miskin, P. Monaghan, R. St-Arnaud, G. L. Smith, and L. K. Dixon (2002)
J. Virol. 76, 9991-9999
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African Swine Fever Virus Protein p54 Interacts with the Microtubular Motor Complex through Direct Binding to Light-Chain Dynein.
C. Alonso, J. Miskin, B. Hernaez, P. Fernandez-Zapatero, L. Soto, C. Canto, I. Rodriguez-Crespo, L. Dixon, and J. M. Escribano (2001)
J. Virol. 75, 9819-9827
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Nuclear Translocation and Activation of the Transcription Factor NFAT Is Blocked by Herpes Simplex Virus Infection.
E. S. Scott, S. Malcomber, and P. O'Hare (2001)
J. Virol. 75, 9955-9965
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Evolutionary relationships among Rel domains indicate functional diversification by recombination.
I. A. Graef, J. M. Gastier, U. Francke, and G. R. Crabtree (2001)
PNAS 98, 5740-5745
   Abstract »    Full Text »    PDF »
Calsarcins, a novel family of sarcomeric calcineurin-binding proteins.
N. Frey, J. A. Richardson, and E. N. Olson (2000)
PNAS
   Abstract »    Full Text »
African Swine Fever Virus Protein A238L Interacts with the Cellular Phosphatase Calcineurin via a Binding Domain Similar to That of NFAT.
J. E. Miskin, C. C. Abrams, and L. K. Dixon (2000)
J. Virol. 74, 9412-9420
   Abstract »    Full Text »
Calcineurin: Form and Function.
F. Rusnak and P. Mertz (2000)
Physiol Rev 80, 1483-1521
   Abstract »    Full Text »    PDF »
ankA: an Ehrlichia phagocytophila Group Gene Encoding a Cytoplasmic Protein Antigen with Ankyrin Repeats.
P. Caturegli, K. M. Asanovich, J. J. Walls, J. S. Bakken, J. E. Madigan, V. L. Popov, and J. S. Dumler (2000)
Infect. Immun. 68, 5277-5283
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DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways.
J. J. Fuentes, L. Genesca, T. J. Kingsbury, K. W. Cunningham, M. Perez-Riba, X. Estivill, and S. d. l. Luna (2000)
Hum. Mol. Genet. 9, 1681-1690
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T. Jayaraman and A. R. Marks (2000)
J. Biol. Chem. 275, 6417-6420
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Regulation of Calcineurin by Growth Cone Calcium Waves Controls Neurite Extension.
N. J. Lautermilch and N. C. Spitzer (2000)
J. Neurosci. 20, 315-325
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Mechanism of Inactivation of NF-kappa B by a Viral Homologue of Ikappa Balpha . SIGNAL-INDUCED RELEASE OF Ikappa Balpha RESULTS IN BINDING OF THE VIRAL HOMOLOGUE TO NF-kappa B.
S. W. G. Tait, E. B. Reid, D. R. Greaves, T. E. Wileman, and P. P. Powell (2000)
J. Biol. Chem. 275, 34656-34664
   Abstract »    Full Text »    PDF »
Calcium, Calcineurin, and the Control of Transcription.
G. R. Crabtree (2001)
J. Biol. Chem. 276, 2313-2316
   Full Text »    PDF »
Calsarcins, a novel family of sarcomeric calcineurin-binding proteins.
N. Frey, J. A. Richardson, and E. N. Olson (2000)
PNAS 97, 14632-14637
   Abstract »    Full Text »    PDF »


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