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Science 1 May 1998: Vol. 280. no. 5364, pp. 734 - 737 DOI: 10.1126/science.280.5364.734
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Reports
Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor
Nicholas S. Duesbery,
Craig P. Webb,
Stephen H. Leppla,
Valery M. Gordon,
Kurt R. Klimpel,
*
Terry D. Copeland,
Natalie G. Ahn,
Marianne K. Oskarsson,
Kenji Fukasawa,
Ken D. Paull,
George F. Vande
Woude
Anthrax lethal toxin, produced by the bacterium Bacillus
anthracis, is the major cause of death in animals infected with
anthrax. One component of this toxin, lethal factor (LF), is suspected to be a metalloprotease, but no physiological substrates have been
identified. Here it is shown that LF is a protease that cleaves the
amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and
inhibits the MAPK signal transduction pathway. The identification of a
cleavage site for LF may facilitate the development of LF inhibitors.
N. S. Duesbery, C. P. Webb, T. D. Copeland, M. K. Oskarsson, G. F. Vande Woude, Advanced BioScience
Laboratories-Basic Research Program, National Cancer
Institute-Frederick Cancer Research and Development Center, Post
Office Box B, Frederick, MD 21702, USA.
S. H. Leppla, V. M. Gordon, K. R. Klimpel, National
Institute of Dental Research-National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
N. G. Ahn, Department of Chemistry and Biochemistry, Howard Hughes
Medical Institute, University of Colorado, Campus Box 215, Boulder, CO
80309, USA.
K. Fukasawa, Department of Cell Biology, University of Cincinnati,
College of Medicine, P.O. Box 670521, Cincinnati, OH 45267, USA.
K. D. Paull, Division of Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
*
Present address: Biopraxis, Post Office Box 9100-78, San Diego,
CA 92191, USA.
To whom correspondence should be addressed.
Read the Full Text
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| PDF »
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- R. W. Bourdeau, E. Malito, A. Chenal, B. L. Bishop, M. W. Musch, M. L. Villereal, E. B. Chang, E. M. Mosser, R. F. Rest, and W.-J. Tang (2009)
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284, 14645-14656
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- Reduced Expression of CD45 Protein-tyrosine Phosphatase Provides Protection against Anthrax Pathogenesis.
- R. G. Panchal, R. L. Ulrich, S. B. Bradfute, D. Lane, G. Ruthel, T. A. Kenny, P. L. Iversen, A. O. Anderson, R. Gussio, W. C. Raschke, et al. (2009)
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284, 12874-12885
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- Anthrax Edema Toxin Induces Maturation of Dendritic Cells and Enhances Chemotaxis towards Macrophage Inflammatory Protein 3{beta}.
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- Direct Inhibition of T-Lymphocyte Activation by Anthrax Toxins In Vivo.
- J. E. Comer, A. K. Chopra, J. W. Peterson, and R. Konig (2005)
Infect. Immun.
73, 8275-8281
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- Whole-cell Voltage Clamp Measurements of Anthrax Toxin Pore Current.
- J. T. Wolfe, B. A. Krantz, G. J. A. Rainey, J. A. T. Young, and R. J. Collier (2005)
J. Biol. Chem.
280, 39417-39422
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- A model of anthrax toxin lethal factor bound to protective antigen.
- D. B. Lacy, H. C. Lin, R. A. Melnyk, O. Schueler-Furman, L. Reither, K. Cunningham, D. Baker, and R. J. Collier (2005)
PNAS
102, 16409-16414
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- Metalloproteinase Inhibitors, Nonantimicrobial Chemically Modified Tetracyclines, and Ilomastat Block Bacillus anthracis Lethal Factor Activity in Viable Cells.
- S. S. Kocer, S. G. Walker, B. Zerler, L. M. Golub, and S. R. Simon (2005)
Infect. Immun.
73, 7548-7557
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- Bacillus anthracis Edema Toxin Causes Extensive Tissue Lesions and Rapid Lethality in Mice.
- A. M. Firoved, G. F. Miller, M. Moayeri, R. Kakkar, Y. Shen, J. F. Wiggins, E. M. McNally, W.-J. Tang, and S. H. Leppla (2005)
Am. J. Pathol.
167, 1309-1320
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- Receptor-specific requirements for anthrax toxin delivery into cells.
- G. J. A. Rainey, D. J. Wigelsworth, P. L. Ryan, H. M. Scobie, R. J. Collier, and J. A. T. Young (2005)
PNAS
102, 13278-13283
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- Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine.
- T. Komiyama, J. A. Swanson, and R. S. Fuller (2005)
Antimicrob. Agents Chemother.
49, 3875-3882
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- BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin.
- R. J. Abi-Habib, J. O. Urieto, S. Liu, S. H. Leppla, N. S. Duesbery, and A. E. Frankel (2005)
Mol. Cancer Ther.
4, 1303-1310
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- Efficient synthetic inhibitors of anthrax lethal factor.
- M. Forino, S. Johnson, T. Y. Wong, D. V. Rozanov, A. Y. Savinov, W. Li, R. Fattorusso, B. Becattini, A. J. Orry, D. Jung, et al. (2005)
PNAS
102, 9499-9504
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- Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin.
- M. Moayeri, J. I. Webster, J. F. Wiggins, S. H. Leppla, and E. M. Sternberg (2005)
Infect. Immun.
73, 4238-4244
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- Membrane Insertion by Anthrax Protective Antigen in Cultured Cells.
- M. Qa'dan, K. A. Christensen, L. Zhang, T. M. Roberts, and R. J. Collier (2005)
Mol. Cell. Biol.
25, 5492-5498
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- Anthrax Lethal Toxin Induces Endothelial Barrier Dysfunction.
- J. M. Warfel, A. D. Steele, and F. D'Agnillo (2005)
Am. J. Pathol.
166, 1871-1881
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- Proteases and Signaling.
- S. Wilk (2005)
Sci. STKE
2005, tr15
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- Dendritic Cells Endocytose Bacillus anthracis Spores: Implications for Anthrax Pathogenesis.
- K. C. Brittingham, G. Ruthel, R. G. Panchal, C. L. Fuller, W. J. Ribot, T. A. Hoover, H. A. Young, A. O. Anderson, and S. Bavari (2005)
J. Immunol.
174, 5545-5552
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- Anthrax Edema Toxin Cooperates with Lethal Toxin to Impair Cytokine Secretion during Infection of Dendritic Cells.
- J.-N. Tournier, A. Quesnel-Hellmann, J. Mathieu, C. Montecucco, W.-J. Tang, M. Mock, D. R. Vidal, and P. L. Goossens (2005)
J. Immunol.
174, 4934-4941
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- Anthrax Lethal Toxin Blocks MAPK Kinase-Dependent IL-2 Production in CD4+ T Cells.
- H. Fang, R. Cordoba-Rodriguez, C. S. R. Lankford, and D. M. Frucht (2005)
J. Immunol.
174, 4966-4971
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- Human {alpha}-defensins neutralize anthrax lethal toxin and protect against its fatal consequences.
- C. Kim, N. Gajendran, H.-W. Mittrucker, M. Weiwad, Y.-H. Song, R. Hurwitz, M. Wilmanns, G. Fischer, and S. H. E. Kaufmann (2005)
PNAS
102, 4830-4835
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- Purified Bacillus anthracis Lethal Toxin Complex Formed in Vitro and during Infection Exhibits Functional and Biological Activity.
- R. G. Panchal, K. M. Halverson, W. Ribot, D. Lane, T. Kenny, T. G. Abshire, J. W. Ezzell, T. A. Hoover, B. Powell, S. Little, et al. (2005)
J. Biol. Chem.
280, 10834-10839
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- GeneChip Analyses of Global Transcriptional Responses of Murine Macrophages to the Lethal Toxin of Bacillus anthracis.
- J. E. Comer, C. L. Galindo, A. K. Chopra, and J. W. Peterson (2005)
Infect. Immun.
73, 1879-1885
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- Bacterial toxins and the immune system: show me the in vivo targets.
- J. E. Galan (2005)
J. Exp. Med.
201, 321-323
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- Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling.
- S. R. Paccani, F. Tonello, R. Ghittoni, M. Natale, L. Muraro, M. M. D'Elios, W.-J. Tang, C. Montecucco, and C. T. Baldari (2005)
J. Exp. Med.
201, 325-331
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- A High-Affinity Monoclonal Antibody to Anthrax Protective Antigen Passively Protects Rabbits before and after Aerosolized Bacillus anthracis Spore Challenge.
- N. Mohamed, M. Clagett, J. Li, S. Jones, S. Pincus, G. D'Alia, L. Nardone, M. Babin, G. Spitalny, and L. Casey (2005)
Infect. Immun.
73, 795-802
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- Murine Macrophage Transcriptional Responses to Bacillus anthracis Infection and Intoxication.
- N. H. Bergman, K. D. Passalacqua, R. Gaspard, L. M. Shetron-Rama, J. Quackenbush, and P. C. Hanna (2005)
Infect. Immun.
73, 1069-1080
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- Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists.
- J. M. Park, V. H. Ng, S. Maeda, R. F. Rest, and M. Karin (2004)
J. Exp. Med.
200, 1647-1655
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- Involvement of Domain II in Toxicity of Anthrax Lethal Factor.
- X. Liang, J. J. Young, S. A. Boone, D. S. Waugh, and N. S. Duesbery (2004)
J. Biol. Chem.
279, 52473-52478
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- Rabbit and Nonhuman Primate Models of Toxin-Targeting Human Anthrax Vaccines.
- A. J. Phipps, C. Premanandan, R. E. Barnewall, and M. D. Lairmore (2004)
Microbiol. Mol. Biol. Rev.
68, 617-629
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- Functional Analysis of Bacillus anthracis Protective Antigen by Using Neutralizing Monoclonal Antibodies.
- F. Brossier, M. Levy, A. Landier, P. Lafaye, and M. Mock (2004)
Infect. Immun.
72, 6313-6317
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- A cationic lipid-formulated plasmid DNA vaccine confers sustained antibody-mediated protection against aerosolized anthrax spores.
- G. Hermanson, V. Whitlow, S. Parker, K. Tonsky, D. Rusalov, M. Ferrari, P. Lalor, M. Komai, R. Mere, M. Bell, et al. (2004)
PNAS
101, 13601-13606
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