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Science 24 September 1999:
Vol. 285. no. 5436, pp. 2129 - 2133
DOI: 10.1126/science.285.5436.2129
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Reports

Affinity-Driven Peptide Selection of an NFAT Inhibitor More Selective Than Cyclosporin A

José Aramburu, 12 Michael B. Yaffe, 3 Cristina López-Rodríguez, 12 Lewis C. Cantley, 4 Patrick G. Hogan, 25* Anjana Rao 12*

The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide libraries based on the calcineurin docking motif of NFAT. This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are less toxic than current drugs.

1 Department of Pathology, Harvard Medical School;
2 The Center for Blood Research, 200 Longwood Avenue, Boston, MA 02115, USA.
3 Division of Signal Transduction, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center;
4 Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, and Department of Cell Biology, Harvard Medical School, Harvard Institutes of Medicine, 330 Brookline Avenue, Boston, MA 02215, USA.
5 CBR Laboratories, 800 Huntington Avenue, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: arao{at}cbr.med.harvard.edu (A.R.); hogan{at}cbr.med.harvard.edu (P.G.H.)

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Requirement of Nuclear Factor of Activated T-cells in Calcineurin-mediated Cardiomyocyte Hypertrophy.
E. van Rooij, P. A. Doevendans, C. C. de Theije, F. A. Babiker, J. D. Molkentin, and L. J. De Windt (2002)
J. Biol. Chem. 277, 48617-48626
   Abstract »    Full Text »    PDF »
Mapping the Protein Phosphatase-2B Anchoring Site on AKAP79. BINDING AND INHIBITION OF PHOSPHATASE ACTIVITY ARE MEDIATED BY RESIDUES 315-360.
M. L. Dell'Acqua, K. L. Dodge, S. J. Tavalin, and J. D. Scott (2002)
J. Biol. Chem. 277, 48796-48802
   Abstract »    Full Text »    PDF »
Direct in Vivo Screening of Intrabody Libraries Constructed on a Highly Stable Single-chain Framework.
A. A. d. Maur, C. Zahnd, F. Fischer, S. Spinelli, A. Honegger, C. Cambillau, D. Escher, A. Pluckthun, and A. Barberis (2002)
J. Biol. Chem. 277, 45075-45085
   Abstract »    Full Text »    PDF »
Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway.
Y. Suzuki, C. Gomez-Guerrero, I. Shirato, O. Lopez-Franco, P. Hernandez-Vargas, G. Sanjuan, M. Ruiz-Ortega, T. Sugaya, K. Okumura, Y. Tomino, et al. (2002)
J. Immunol. 169, 4136-4146
   Abstract »    Full Text »    PDF »
Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6. ROLE FOR CYCLIC AMP-RESPONSIVE ELEMENT-BINDING PROTEIN AND ACTIVATOR PROTEIN-1.
M.-E. Janelle, A. Gravel, J. Gosselin, M. J. Tremblay, and L. Flamand (2002)
J. Biol. Chem. 277, 30665-30674
   Abstract »    Full Text »    PDF »
Multiple Domains of MCIP1 Contribute to Inhibition of Calcineurin Activity.
R. B. Vega, J. Yang, B. A. Rothermel, R. Bassel-Duby, and R. S. Williams (2002)
J. Biol. Chem. 277, 30401-30407
   Abstract »    Full Text »    PDF »
Characters in context: molluscan shells and the forces that mold them.
(2002)
Paleobiology 28, 41-54
Requirement of Two NFATc4 Transactivation Domains for CBP Potentiation.
T. Yang, R. J. Davis, and C.-W. Chow (2001)
J. Biol. Chem. 276, 39569-39576
   Abstract »    Full Text »    PDF »
Inhibition of NFATx Activation by an Oligopeptide: Disrupting the Interaction of NFATx with Calcineurin.
J. Liu, K.-i. Arai, and N. Arai (2001)
J. Immunol. 167, 2677-2687
   Abstract »    Full Text »    PDF »
Regulation of interferon-{gamma} gene expression by nuclear factor of activated T cells.
A. Kiani, F. J. Garcia-Cozar, I. Habermann, S. Laforsch, T. Aebischer, G. Ehninger, and A. Rao (2001)
Blood 98, 1480-1488
   Abstract »    Full Text »    PDF »
Regulation of Myosin Heavy Chain Expression during Rat Skeletal Muscle Development In Vitro.
C. E. Torgan and M. P. Daniels (2001)
Mol. Biol. Cell 12, 1499-1508
   Abstract »    Full Text »
Identification of novel chemoattractant peptides for human leukocytes.
Y.-S. Bae, H. Bae, Y. Kim, T. G. Lee, P.-G. Suh, and S. H. Ryu (2001)
Blood 97, 2854-2862
   Abstract »    Full Text »    PDF »
Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus.
J. P. Zoeteweij, A. V. Moses, A. S. Rinderknecht, D. A. Davis, W. W. Overwijk, R. Yarchoan, J. M. Orenstein, and A. Blauvelt (2001)
Blood 97, 2374-2380
   Abstract »    Full Text »    PDF »
Selective Inhibition of Vascular Endothelial Growth Factor-Mediated Angiogenesis by Cyclosporin a: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2.
G. L. Hernandez, O. V. Volpert, M. A. Iniguez, E. Lorenzo, S. Martinez-Martinez, R. Grau, M. Fresno, and J. M. Redondo (2001)
J. Exp. Med. 193, 607-620
   Abstract »    Full Text »    PDF »
A calcineurin- and NFAT-dependent pathway regulates Myf5 gene expression in skeletal muscle reserve cells.
B. Friday and G. Pavlath (2001)
J. Cell Sci. 114, 303-310
   Abstract »    PDF »
Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo.
S. Silletti, T. Kessler, J. Goldberg, D. L. Boger, and D. A. Cheresh (2000)
PNAS
   Abstract »    Full Text »
Evidence That Galpha q-Coupled Receptor-Induced Interleukin-6 mRNA in Vascular Smooth Muscle Cells Involves the Nuclear Factor of Activated T Cells.
K. L. Abbott, J. R. Loss II, A. M. Robida, and T. J. Murphy (2000)
Mol. Pharmacol. 58, 946-953
   Abstract »    Full Text »
Calcineurin and Beyond : Cardiac Hypertrophic Signaling.
J. D. Molkentin (2000)
Circ. Res. 87, 731-738
   Abstract »    Full Text »    PDF »
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 »
Cyclosporin A Selectively Inhibits Mitogen-Induced Cyclooxygenase-2 Gene Transcription in Vascular Smooth Muscle Cells.
A. M. Robida, K. Xu, M. L. Ellington, and T. J. Murphy (2000)
Mol. Pharmacol. 58, 701-708
   Abstract »    Full Text »


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