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
Fluid support worsens outcome and negates the benefit of protective antigen-directed monoclonal antibody in a lethal toxin-infused rat Bacillus anthracis shock model.
Kevin Sherer,Yan Li,Xizhong Cui,Xuemei Li,Mani Subramanian,Michael W. Laird,Michael W. Laird,Mahtab Moayeri,Stephen H. Leppla,Yvonne Fitz,Junwu Su,Peter Q. Eichacker +11 more
TL;DR: These findings raise the possibility that normal saline treatment may actually worsen outcome with anthrax lethal toxin, and lethal toxin-directed therapies may not be as beneficial when used in combination with this type of fluid support.
Journal ArticleDOI
Resistance of Human Alveolar Macrophages to Bacillus anthracis Lethal Toxin
Wenxin Wu,Harshini Mehta,Kaushik Chakrabarty,J. Leland Booth,Elizabeth S. Duggan,Krupa B. Patel,Jimmy D. Ballard,K. Mark Coggeshall,Jordan P. Metcalf +8 more
TL;DR: AM resistance to LT may enhance clearance of the pathogen from the alveolar surface and explain why this surface is relatively free of B. anthracis in animal models and autopsy studies.
Journal ArticleDOI
Exploring the role of host cell chaperones/PPIases during cellular up-take of bacterial ADP-ribosylating toxins as basis for novel pharmacological strategies to protect mammalian cells against these virulence factors
TL;DR: Investigation of the cellular uptake of the binary actin ADP-ribosylating C2 toxin from Clostridium botulinum and the binary lethal toxin from Bacillus anthracis finds that Hsp90 and cyclophilin function selectively in promoting translocation of certain bacterial toxins depending on the enzyme domains of the individual toxins.
Journal ArticleDOI
Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors.
Philip Förstner,Fabienne Bayer,Nnanya Kalu,Susanne Felsen,Christina Förtsch,Abrar Aloufi,David Y. W. Ng,Tanja Weil,Ekaterina M. Nestorovich,Holger Barth +9 more
TL;DR: It is demonstrated that at low μM concentrations cationic PAMAM dendrimers block PA63 and C2IIa to inhibit channel-mediated transport of the A components, thereby protecting HeLa and Vero cells from intoxication.
Journal ArticleDOI
Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein–Coupled Receptor
Philippe Depeille,Philippe Depeille,John J. Young,Elissa Boguslawski,Bree Berghuis,Eric J. Kort,James H. Resau,Arthur E. Frankel,Nicholas S. Duesbery +8 more
TL;DR: Data support a role for MKK signaling in tumor growth and vascularization and are consistent with the hypothesis that inhibition of MKK signaled by LeTx or a similar agent may be an effective strategy for the treatment of Kaposi's sarcoma as well as other vascular tumors.
References
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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.