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
Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system
Yan Li,Mones Abu-Asab,Junwu Su,Ping Qiu,Jing Feng,Lernik Ohanjanian,Hanish Sampath Kumar,Yvonne Fitz,Peter Q. Eichacker,Xizhong Cui +9 more
TL;DR: In vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts, and while lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia.
Journal ArticleDOI
Selective targeting of metastatic ovarian cancer using an engineered anthrax prodrug activated by membrane-anchored serine proteases
Nadire Duru,Nisha R. Pawar,Erik W. Martin,Marguerite S. Buzza,Gregory D. Conway,Rena G. Lapidus,Shihui Liu,Jocelyn Reader,Gautam G. Rao,Dana M. Roque,Stephen H. Leppla,Toni M. Antalis +11 more
TL;DR: The basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death is developed.
Journal ArticleDOI
Cross-inhibition of pathogenic agents and the host proteins they exploit.
Leeor Zilbermintz,William Leonardi,Sharon H. Tran,Josue Zozaya,Alyssa Mathew-Joseph,Spencer Liem,Anastasia Levitin,Mikhail Martchenko +7 more
TL;DR: Two approved drugs are identified that effectively inhibited anthrax cytotoxic protease and demonstrated that they also block proteolytic activities of host furin, cathepsin B, and caspases that mediate toxin’s lethality in cells.
Journal ArticleDOI
Protein Kinase R in Bacterial Infections: Friend or Foe?
Robin Smyth,Jim Sun +1 more
TL;DR: An overview of immune cell functions regulated by PKR is provided and the current knowledge on the role and functions of PKR in bacterial infections is summarized and existing pharmacological modulators of PKr that could be explored as novel treatment strategies for bacterial infections are provided.
Book ChapterDOI
Multivalent Inhibitors of Channel-Forming Bacterial Toxins.
TL;DR: Several prominent examples where the multivalent blockers were investigated for their ability to directly obstruct oligomeric channel-forming bacterial exotoxins, such as the pore-formingacterial toxins and B component of the binary bacterial toxins are described.
References
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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
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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.