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Science 29 October 1993:
Vol. 262. no. 5134, pp. 750 - 754
DOI: 10.1126/science.8235597
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Articles

Science, Vol 262, Issue 5134, 750-754
Copyright © 1993 by American Association for the Advancement of Science

articles

Isolation of the cyclosporin-sensitive T cell transcription factor NFATp

PG McCaffrey, C Luo, TK Kerppola, J Jain, TM Badalian, AM Ho, E Burgeon, WS Lane, JN Lambert, T Curran, and al. et

Division of Tumor Virology, Dana-Farber Cancer Institute, Boston, MA.

Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells. The DNA-binding specificity of NFAT is conferred by NFATp, a phosphoprotein that is a target for the immunosuppressive compounds cyclosporin A and FK506. Here, the purification of NFATp from murine T cells and the isolation of a complementary DNA clone encoding NFATp are reported. A truncated form of NFATp, expressed as a recombinant protein in bacteria, binds specifically to the NFAT site of the murine IL-2 promoter and forms a transcriptionally active complex with recombinant protein fragment react with T cell NFATp. The molecular cloning of NFATp should allow detailed analysis of a T cell transcription factor that is central to initiation of the immune response.


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Cutting Edge: Expression of the NF of Activated T Cells in Eosinophils: Regulation by IL-4 and IL-5.
T. Jinquan, S. Quan, H. H. Jacobi, C. M. Reimert, A. Millner, J. B. Hansen, C. Thygesen, L. P. Ryder, H. O. Madsen, H.-J. Malling, et al. (1999)
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P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells.
D. Ferrari, C. Stroh, and K. Schulze-Osthoff (1999)
J. Biol. Chem. 274, 13205-13210
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Reciprocal Modulatory Interaction between Human Immunodeficiency Virus Type 1 Tat and Transcription Factor NFAT1.
F. Macian and A. Rao (1999)
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Two Independent Calcineurin-Binding Regions in the N-Terminal Domain of Murine NF-ATx1 Recruit Calcineurin to Murine NF-ATx1.
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J. Immunol. 162, 4755-4761
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Prevention of Cardiac Hypertrophy by Calcineurin Inhibition : Hope or Hype?.
E. N. Olson and J. D. Molkentin (1999)
Circ. Res. 84, 623-632
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Requirement for Transcription Factor NFAT in Interleukin-2 Expression.
C.-W. Chow, M. Rincon, and R. J. Davis (1999)
Mol. Cell. Biol. 19, 2300-2307
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NF-ATc Isoforms Are Differentially Expressed and Regulated in Murine T and Mast Cells.
M. A. Sherman, D. R. Powell, D. L. Weiss, and M. A. Brown (1999)
J. Immunol. 162, 2820-2828
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Characterization of a Novel Calcium Response Element in the Glucagon Gene.
U. Furstenau, M. Schwaninger, R. Blume, E.-M. Jendrusch, and W. Knepel (1999)
J. Biol. Chem. 274, 5851-5860
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Rapamycin Causes Poorly Reversible Inhibition of mTOR and Induces p53-independent Apoptosis in Human Rhabdomyosarcoma Cells.
H. Hosoi, M. B. Dilling, T. Shikata, L. N. Liu, L. Shu, R. A. Ashmun, G. S. Germain, R. T. Abraham, and P. J. Houghton (1999)
Cancer Res. 59, 886-894
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T Cell Priming Enhances IL-4 Gene Expression by Increasing Nuclear Factor of Activated T Cells.
R. Q. Cron, S. J. Bort, Y. Wang, M. W. Brunvand, and D. B. Lewis (1999)
J. Immunol. 162, 860-870
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Signaling through Calcium, Calcineurin, and NF-AT in Lymphocyte Activation and Development.
K. STANKUNAS, I.A. GRAEF, J.R. NEILSON, S.-H. PARK, and G.R. CRABTREE (1999)
Cold Spring Harb Symp Quant Biol 64, 505-516
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NF-AT5: The NF-AT Family of Transcription Factors Expands in a New Direction.
C. LOPEZ-RODRIGUEZ, J. ARAMBURU, A.S. RAKEMAN, N.G. COPELAND, D.J. GILBERT, S. THOMAS, C. DISTECHE, N.A. JENKINS, and A. RAO (1999)
Cold Spring Harb Symp Quant Biol 64, 517-526
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Signal Integration by Transcription-factor Assemblies: Interactions of NF-AT1 and AP-1 on the IL-2 Promoter.
L. CHEN, A. RAO, and S.C. HARRISON (1999)
Cold Spring Harb Symp Quant Biol 64, 527-532
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Tissue-specific Regulation of Cytokine Gene Expression.
I.-C. HO, J.I. KIM, S.J. SZABO, and L.H. GLIMCHER (1999)
Cold Spring Harb Symp Quant Biol 64, 573-584
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The Roles of Nuclear Factor of Activated T Cells and Ying-Yang 1 in Activation-induced Expression of the Interferon-gamma Promoter in T Cells.
M. T. Sweetser, T. Hoey, Y.-L. Sun, W. M. Weaver, G. A. Price, and C. B. Wilson (1998)
J. Biol. Chem. 273, 34775-34783
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I-C. Ho, J. H.-J. Kim, J. W. Rooney, B. M. Spiegelman, and L. H. Glimcher (1998)
PNAS 95, 15537-15541
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Utilization of an NF-ATp Binding Promoter Element for EGR3 Expression in T Cells but Not Fibroblasts Provides a Molecular Model for the Lymphoid Cell-Specific Effect of Cyclosporin A.
H. W. Mages, R. Baag, B. Steiner, and R. A. Kroczek (1998)
Mol. Cell. Biol. 18, 7157-7165
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Studies on the Mechanism of Resistance to Rapamycin in Human Cancer Cells.
H. Hosoi, M. B. Dilling, L. N. Liu, M. K. Danks, T. Shikata, A. Sekulic, R. T. Abraham, J. C. Lawrence Jr., and P. J. Houghton (1998)
Mol. Pharmacol. 54, 815-824
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AKAP79 Inhibits Calcineurin through a Site Distinct from the Immunophilin-binding Region.
A. Kashishian, M. Howard, C. Loh, W. M. Gallatin, M. F. Hoekstra, and Y. Lai (1998)
J. Biol. Chem. 273, 27412-27419
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Carboxyl-Terminal 15-Amino Acid Sequence of NFATx1 Is Possibly Created by Tissue-Specific Splicing and Is Essential for Transactivation Activity in T Cells.
R. Imamura, E. S. Masuda, Y. Naito, S.-i. Imai, T. Fujino, T. Takano, K.-i. Arai, and N. Arai (1998)
J. Immunol. 161, 3455-3463
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Two-site Interaction of Nuclear Factor of Activated T Cells with Activated Calcineurin.
F. J. Garcia-Cozar, H. Okamura, J. F. Aramburu, K. T. Y. Shaw, L. Pelletier, R. Showalter, E. Villafranca, and A. Rao (1998)
J. Biol. Chem. 273, 23877-23883
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Involvement of NF-AT in Type I Human T-cell Leukemia Virus Tax-mediated Fas Ligand Promoter Transactivation.
I. Rivera, E. W. Harhaj, and S.-C. Sun (1998)
J. Biol. Chem. 273, 22382-22388
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V. Boss, K. L. Abbott, X.-F. Wang, G. K. Pavlath, and T. J. Murphy (1998)
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Molecular basis of cooperative DNA bending and oriented heterodimer binding in the NFAT1---Fos-Jun---ARRE2 complex.
R. J. Diebold, N. Rajaram, D. A. Leonard, and T. K. Kerppola (1998)
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Inhibition of Phosphodiesterase Type IV Suppresses Human Immunodeficiency Virus Type 1 Replication and Cytokine Production in Primary T Cells: Involvement of NF-kappa B and NFAT.
J. Navarro, C. Punzon, J. L. Jimenez, E. Fernandez-Cruz, A. Pizarro, M. Fresno, and M. A. Munoz-Fernandez (1998)
J. Virol. 72, 4712-4720
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The HMG Domain Protein SSRP1/PREIIBF Is Involved in Activation of the Human Embryonic beta -Like Globin Gene.
M. A. Dyer, P. J. Hayes, and M. H. Baron (1998)
Mol. Cell. Biol. 18, 2617-2628
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Transcriptional Repression of the IL-2 Gene in Th Cells by ZEB.
D. H. Yasui, T. Genetta, T. Kadesch, T. M. Williams, S. L. Swain, L. V. Tsui, and B. T. Huber (1998)
J. Immunol. 160, 4433-4440
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Granulocyte-Macrophage Colony-stimulating Factor Gene Transcription Is Directly Repressed by the Vitamin D3 Receptor. IMPLICATIONS FOR ALLOSTERIC INFLUENCES ON NUCLEAR RECEPTOR STRUCTURE AND FUNCTION BY A DNA ELEMENT.
T. L. Towers and L. P. Freedman (1998)
J. Biol. Chem. 273, 10338-10348
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Distinct NFAT Family Proteins Are Involved in the Nuclear NFAT-DNA Binding Complexes from Human Thymocyte Subsets.
Y. Amasaki, E. S. Masuda, R. Imamura, K.-i. Arai, and N. Arai (1998)
J. Immunol. 160, 2324-2333
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Nuclear Factor of Activated T Cells (NFAT) as a Molecular Target for 1{alpha},25-Dihydroxyvitamin D3-Mediated Effects.
A. Takeuchi, G. S. Reddy, T. Kobayashi, T. Okano, J. Park, and S. Sharma (1998)
J. Immunol. 160, 209-218
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Two NFAT Transcription Factor Binding Sites Participate in the Regulation of CD95 (Fas) Ligand Expression in Activated Human T Cells.
K. M. Latinis, L. A. Norian, S. L. Eliason, and G. A. Koretzky (1997)
J. Biol. Chem. 272, 31427-31434
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The Ca2+/Calmodulin-dependent Kinase Type IV Is Involved in the CD5-mediated Signaling Pathway in Human T Lymphocytes.
S. I. Gringhuis, L. F. M. H. de Leij, G. A. Wayman, H. Tokumitsu, and E. Vellenga (1997)
J. Biol. Chem. 272, 31809-31820
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Interaction of NF-kappa B and NFAT with the Interferon-gamma Promoter.
A. Sica, L. Dorman, V. Viggiano, M. Cippitelli, P. Ghosh, N. Rice, and H. A. Young (1997)
J. Biol. Chem. 272, 30412-30420
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FK-506 and Cyclosporin A Potentiate the IgE Antibody Production by Contact Sensitization with Hapten in Mice.
H. Nagai, H. Hiyama, A. Matsuo, Y. Ueda, N. Inagaki, and K. Kawada (1997)
J. Pharmacol. Exp. Ther. 283, 321-327
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Interleukin-7 Upregulates the Interleukin-2-Gene Expression in Activated Human T Lymphocytes at the Transcriptional Level by Enhancing the DNA Binding Activities of Both Nuclear Factor of Activated T Cells and Activator Protein-1.
S. I. Gringhuis, L. F.M.H. de Leij, E. W. Verschuren, P. Borger, and E. Vellenga (1997)
Blood 90, 2690-2700
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Identification of Transcription Factor Binding Sites Important in the Regulation of the Human Interleukin-5 Gene.
K. S. Stranick, D. N. Zambas, A. S. Uss, R. W. Egan, M. M. Billah, and S. P. Umland (1997)
J. Biol. Chem. 272, 16453-16465
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Dual role of the nuclear factor of activated T cells insert region in DNA recognition and cooperative contacts to activator protein 1.
L. J. Sun, B. R. Peterson, and G. L. Verdine (1997)
PNAS 94, 4919-4924
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Constitutive Binding of the Transcription Factor Interleukin-2 (IL-2) Enhancer Binding Factor to the IL-2 Promoter.
A. Nirula, D. J. Moore, and R. B. Gaynor (1997)
J. Biol. Chem. 272, 7736-7745
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Constitutive Dephosphorylation and Activation of a Member of the Nuclear Factor of Activated T Cells, NF-AT1, in Tax-expressing and Type I Human T-cell Leukemia Virus-infected Human T Cells.
L. Good, S. B. Maggirwar, E. W. Harhaj, and S.-C. Sun (1997)
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Intronic Enhancer Activity of the Eosinophil-derived Neurotoxin (RNS2) and Eosinophil Cationic Protein (RNS3) Genes Is Mediated by an NFAT-1 Consensus Binding Sequence.
J. S. Handen and H. F. Rosenberg (1997)
J. Biol. Chem. 272, 1665-1669
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HMG I(Y) interferes with the DNA binding of NF-AT factors and the induction of the interleukin 4 promoter in T cells.
S. Klein-Hessling, G. Schneider, A. Heinfling, S. Chuvpilo, and E. Serfling (1996)
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A critical arginine residue mediates cooperativity in the contact interface between transcription factors NFAT and AP-1.
B. R. Peterson, L. J. Sun, and G. L. Verdine (1996)
PNAS 93, 13671-13676
   Abstract »    Full Text »    PDF »
Characterization of a New Isoform of the NFAT (Nuclear Factor of Activated T Cells) Gene Family Member NFATc.
J. Park, A. Takeuchi, and S. Sharma (1996)
J. Biol. Chem. 271, 20914-20921
   Abstract »    Full Text »    PDF »
Calcineurin Binds the Transcription Factor NFAT1 and Reversibly Regulates Its Activity.
C. Loh, K. T.-Y. Shaw, J. Carew, J. P. B. Viola, C. Luo, B. A. Perrino, and A. Rao (1996)
J. Biol. Chem. 271, 10884-10891
   Abstract »    Full Text »    PDF »
Interactions of a Transcriptional Activator in the env Gene of the Mouse Mammary Tumor Virus with Activation-dependent, T Cell-specific Transacting Factors.
D. Sambasivarao and V. Paetkau (1996)
J. Biol. Chem. 271, 8942-8950
   Abstract »    Full Text »    PDF »
Transcriptional Regulation of the Interleukin-2 Gene in Normal Human Peripheral Blood T Cells.
C. C. W. Hughes and J. S. Pober (1996)
J. Biol. Chem. 271, 5369-5377
   Abstract »    Full Text »    PDF »
The CD40L Promoter Contains Nuclear Factor of Activated T Cells-binding Motifs Which Require AP-1 Binding for Activation of Transcription.
A. V. Tsytsykova, E. N. Tsitsikov, and R. S. Geha (1996)
J. Biol. Chem. 271, 3763-3770
   Abstract »    Full Text »    PDF »
Identification of a Physical Interaction between Calcineurin and Nuclear Factor of Activated T Cells (NFATp).
S. Wesselborg, D. A. Fruman, J. K. Sagoo, B. E. Bierer, and S. J. Burakoff (1996)
J. Biol. Chem. 271, 1274-1277
   Abstract »    Full Text »    PDF »
The Human gp39 Promoter.
L. A. Schubert, G. King, R. Q. Cron, D. B. Lewis, A. Aruffo, and D. Hollenbaugh (1995)
J. Biol. Chem. 270, 29624-29627
   Abstract »    Full Text »    PDF »
TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin.
M. C. Lorenz and J. Heitman (1995)
J. Biol. Chem. 270, 27531-27537
   Abstract »    Full Text »    PDF »
Identification of a Novel Repressive Element in the Proximal lck Promoter.
R. C. Muise-Helmericks and N. Rosen (1995)
J. Biol. Chem. 270, 27538-27543
   Abstract »    Full Text »    PDF »
A Regulatory Element in the Human Interleukin 2 Gene Promoter Is a Binding Site for the Zinc Finger Proteins Sp1 and EGR-1.
C. Skerka, E. L. Decker, and P. F. Zipfel (1995)
J. Biol. Chem. 270, 22500-22506
   Abstract »    Full Text »    PDF »
Direct Demonstration of NFAT(p) Dephosphorylation and Nuclear Localization in Activated HT-2 Cells Using a Specific NFAT(p) Polyclonal Antibody.
V. A. Ruff and K. L. Leach (1995)
J. Biol. Chem. 270, 22602-22607
   Abstract »    Full Text »    PDF »
Phosphorylation of the Transcription Factor NFATp Inhibits Its DNA Binding Activity in Cyclosporin A-treated Human B and T Cells.
J. Park, N. R. Yaseen, P. G. Hogan, A. Rao, and S. Sharma (1995)
J. Biol. Chem. 270, 20653-20659
   Abstract »    Full Text »    PDF »
NFATc3, a Lymphoid-specific NFATc Family Member That Is Calcium-regulated and Exhibits Distinct DNA Binding Specificity.
S. N. Ho, D. J. Thomas, L. A. Timmerman, X. Li, U. Francke, and G. R. Crabtree (1995)
J. Biol. Chem. 270, 19898-19907
   Abstract »    Full Text »    PDF »
Definition of cis-Regulatory Elements of the Mouse Interleukin-5 Gene Promoter.
H. J. Lee, E. S. Masuda, N. Arai, K.-i. Arai, and T. Yokota (1995)
J. Biol. Chem. 270, 17541-17550
   Abstract »    Full Text »    PDF »
Fc[IMAGE]RI-mediated Induction of Nuclear Factor of Activated T-cells.
L. E. Hutchinson and M. A. McCloskey (1995)
J. Biol. Chem. 270, 16333-16338
   Abstract »    Full Text »    PDF »


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