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
Serodiagnosis of Human Cutaneous Anthrax in India Using an Indirect Anti-Lethal Factor IgG Enzyme-Linked Immunosorbent Assay
TL;DR: The ELISA could be a very useful tool for early diagnosis of cutaneous anthrax cases, as antibodies against LF appear much earlier than those against other anthrax toxins in human serum samples.
Journal ArticleDOI
CCT chaperonin complex is required for efficient delivery of anthrax toxin into the cytosol of host cells
Louise H. Slater,Erik C. Hett,Erik C. Hett,Anne E. Clatworthy,Anne E. Clatworthy,Kevin G. Mark,Kevin G. Mark,Deborah T. Hung,Deborah T. Hung +8 more
TL;DR: A high-throughput shRNA screen to identify host factors required for anthrax lethal toxin-induced cell death suggests that CCT is required for efficient delivery of enzymatically active toxin to the cytosol and is consistent with a direct role for CCT in translocation of LF through the protective antigen pore.
Journal ArticleDOI
In vivo dynamics of active edema and lethal factors during anthrax.
Clémence Rougeaux,François Becher,Eric Ezan,Jean-Nicolas Tournier,Jean-Nicolas Tournier,Pierre L. Goossens +5 more
TL;DR: In this study, the in vivo kinetics of production of the toxin components EF (edema factor) and LF (lethal factor) during cutaneous infection with a wild-type toxinogenic encapsulated strain in immuno-competent mice are unraveled for the first time.
Patent
[3.2.0] Heterocyclic compounds and methods of using the same
Barbara C. M. Potts,Venkata Rami Reddy Macherla,Scott S Mitchell,Rama Rao Manam,Katherine Anne Reed,Kin S. Lam,Saskia T. C. Neuteboom,Ta-Hsiang Chao,Benjamin Nicholson,Cheryl Billstrom +9 more
TL;DR: In this paper, compounds of Formulae I-VI and derivatives thereof having anti-cancer, anti-inflammatory, and anti-microbial properties and compositions that include one or more of compounds and their derivatives or analogs having anti cancer, anti inflammatory conditions, and microbial infections with the disclosed compounds or the disclosed pharmaceutical compositions are disclosed.
Journal ArticleDOI
Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain.
Guan-Sheng Jiao,Seongjin Kim,Mahtab Moayeri,Devorah Crown,April Thai,Lynne Cregar-Hernandez,Linda McKasson,Banumathi Sankaran,Axel T. Lehrer,Teri Wong,Lisa Johns,Stephen A. Margosiak,Stephen H. Leppla,Alan T. Johnson +13 more
TL;DR: Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication.
References
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A synthetic inhibitor of the mitogen-activated protein kinase cascade.
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Cyclin is degraded by the ubiquitin pathway
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Transformation of mammalian cells by constitutively active MAP kinase kinase
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
TL;DR: It is found that constitutive activation of MAPKK is sufficient to promote cell transformation and is associated with highly tumorigenic in nude mice.
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.