Journal ArticleDOI
Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor
Nicholas S. Duesbery,Craig P. Webb,Stephen H. Leppla,Valery M. Gordon,Kurt Klimpel,Terry D. Copeland,Natalie G. Ahn,M Oskarsson,Kenji Fukasawa,Ken D. Paull,George F. Vande Woude +10 more
TLDR
It is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway.Abstract:
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.read more
Citations
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Journal ArticleDOI
General Aspects and Recent Advances on Bacterial Protein Toxins
TL;DR: Understanding the mechanisms of toxin action provides a basis to develop vaccines and therapies to combat bacterial pathogens and to develop new strategies to use toxin derivatives for the treatment of human disease.
Journal ArticleDOI
Anthrax toxin receptor 2-dependent lethal toxin killing in vivo.
Heather M. Scobie,Heather M. Scobie,Darran J. Wigelsworth,John M. Marlett,Diane Thomas,G. Jonah A. Rainey,D. Borden Lacy,Marianne Manchester,R. John Collier,John A. T. Young +9 more
TL;DR: A D683K mutant form of PA that bound specifically to human and rat AN TXR2 mediated killing of rats by anthrax lethal toxin, providing strong evidence for the physiological importance of ANTXR2 in anthrax disease pathogenesis.
Journal ArticleDOI
Antiplatelet activities of anthrax lethal toxin are associated with suppressed p42/44 and p38 mitogen-activated protein kinase pathways in the platelets.
Jyh-Hwa Kau,Der-Shan Sun,Wei-Jern Tsai,Huey-Fen Shyu,Hsin-Hsien Huang,Hung-Chi Lin,Hsin-Hou Chang +6 more
TL;DR: The data suggest that platelets are a pathogenic target for anthrax LT, and combined treatments with LT and antiplatelet agents such as aspirin and the RGD-containing disintegrin rhodostomin significantly increased mortality in mice.
Journal ArticleDOI
Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax
Chandra C. Ghosh,Aditi Mukherjee,Sascha David,Ulla G. Knaus,Deborah J. Stearns-Kurosawa,Shinichiro Kurosawa,Samir M. Parikh +6 more
TL;DR: It is found that LT challenge in mice disrupts signaling through Tie-2, a tonically activated receptor tyrosine kinase in the endothelium, thereby weakening the vascular barrier and contributing to lethality of the disease.
Epidemiology, Diagnosis, and Management
TL;DR: The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure, culminating in septic shock, respiratory distress, and death within 24 h.
References
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Sam J. Mansour,W. T. Matten,April S. Hermann,Julian M. Candia,Sing Rong,Kenji Fukasawa,G F Vande Woude,Natalie G. Ahn +7 more
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Journal ArticleDOI
Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells.
TL;DR: It is shown here that EF is an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1] produced by Bacillus anthracis in an inactive form and nearly equals that of the most active known cyclase.
Journal ArticleDOI
Multiple Ras functions can contribute to mammalian cell transformation.
Michael A. White,Charles Nicolette,Audrey Minden,Anthony Polverino,Linda Van Aelst,Michael Karin,Michael Wigler +6 more
TL;DR: Results indicate that multiple cellular components, including Raf1, are activated by Ha-Ras and contribute to Ha- Ras-induced mammalian cell transformation.