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Journal ArticleDOI

Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor

01 May 1998-Science (American Association for the Advancement of Science)-Vol. 280, Iss: 5364, pp 734-737
TL;DR: 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.
Citations
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Journal ArticleDOI
13 Oct 2000-Cell
TL;DR: This review will focus on the JNK group of MAP kinases, which are characterized by the sequence TEY and the two stress-activatedMAP kinases: p38 with the sequence TGY, and the c-Jun NH2-terminal kinases (JNK) with the sequences TPY.

4,228 citations


Cites background from "Proteolytic Inactivation of MAP-Kin..."

  • ...…be inactivated during infection of cells with pathogens; foris a physiologically relevant activator of p38 MAPK is unclear because p38 MAPK is also activated by MKK3 example, by the Yersinia pestis virulence factor, YpoJ, and anthrax lethal factor (Duesbery et al., 1998; Orth etand MKK6 (Figure 1)....

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Journal ArticleDOI
TL;DR: Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted and particular emphasis is on ERK1/2.
Abstract: Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.

4,040 citations

Journal ArticleDOI
TL;DR: The development, use and productivity of the NCI60 screen are reviewed, highlighting several outcomes that have contributed to advances in cancer chemotherapy.
Abstract: The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

2,257 citations


Cites methods from "Proteolytic Inactivation of MAP-Kin..."

  • ...The pattern of cellular sensitivity was found using COMPARE to correlate closely with that produced by PD98059, a known inhibitor of the mitogen-activated ERK kinase (MEK) pathwa...

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Journal ArticleDOI
TL;DR: It is proposed that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability.
Abstract: Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alternative approach is to target functions essential for infection, such as virulence factors required to cause host damage and disease. This approach has several potential advantages including expanding the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in decreased resistance. We review new approaches to targeting virulence, discuss their advantages and disadvantages, and propose that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability. We highlight both new advances in identifying these functions and prospects for antimicrobial discovery targeting this unexploited area.

1,231 citations


Cites background from "Proteolytic Inactivation of MAP-Kin..."

  • ...LF can also cleave the N termini of several mitogen-activated protein (MAP) kinase kinase...

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Journal ArticleDOI
TL;DR: Only a few low molecular mass signals, including jasmonic acid, ethylene and salicylic acid, upregulate the expression of scores of defense-related genes, which fine-tunes its defense gene expression against aggressors.

1,008 citations

References
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Journal ArticleDOI
TL;DR: Results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype and PD 098059 is an invaluable tool that will help elucidate the role of theMAPK cascade in a variety of biological settings.
Abstract: Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.

2,697 citations

Journal ArticleDOI
10 Jan 1991-Nature
TL;DR: Cyclin degradation is the key step governing exit from mitosis and progress into the next cell cycle, and anaphase may be triggered by the recognition of cyclin by the ubiquitin-conjugating system.
Abstract: Cyclin degradation is the key step governing exit from mitosis and progress into the next cell cycle. When a region in the N terminus of cyclin is fused to a foreign protein, it produces a hybrid protein susceptible to proteolysis at mitosis. During the course of degradation, both cyclin and the hybrid form conjugates with ubiquitin. The kinetic properties of the conjugates indicate that cyclin is degraded by ubiquitin-dependent proteolysis. Thus anaphase may be triggered by the recognition of cyclin by the ubiquitin-conjugating system.

2,372 citations

Journal ArticleDOI
12 Aug 1994-Science
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.
Abstract: Mitogen-activated protein (MAP) kinase kinase (MAPKK) activates MAP kinase in a signal transduction pathway that mediates cellular responses to growth and differentiation factors. Oncogenes such as ras, src, raf, and mos have been proposed to transform cells by prolonging the activated state of MAPKK and of components downstream in the signaling pathway. To test this hypothesis, constitutively active MAPKK mutants were designed that had basal activities up to 400 times greater than that of the unphosphorylated wild-type kinase. Expression of these mutants in mammalian cells activated AP-1-regulated transcription. The cells formed transformed foci, grew efficiently in soft agar, and were highly tumorigenic in nude mice. These findings indicate that constitutive activation of MAPKK is sufficient to promote cell transformation.

1,301 citations

Journal ArticleDOI
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.
Abstract: Anthrax toxin is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). These proteins individually cause no known physiological effects in animals but in pairs produce two toxic actions. Injection of PA with LF causes death of rats in 60 min, whereas PA with EF causes edema in the skin of rabbits and guinea pigs. The mechanisms of action of these proteins have not been determined. It is shown here that EF is an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] produced by Bacillus anthracis in an inactive form. Activation occurs upon contact with a heat-stable eukaryotic cell material. The specific activity of the resulting adenylate cyclase nearly equals that of the most active known cyclase. In Chinese hamster ovary cells exposed to PA and EF, cAMP concentrations increase without a lag to values about 200-fold above normal, remain high in the continued presence of toxin, and decrease rapidly after its removal. The increase in cAMP is completely blocked by excess LF. It is suggested that PA interacts with cells to form a receptor system by which EF and perhaps LF gain access to the cytoplasm.

926 citations

Journal ArticleDOI
24 Feb 1995-Cell
TL;DR: Results indicate that multiple cellular components, including Raf1, are activated by Ha-Ras and contribute to Ha- Ras-induced mammalian cell transformation.

674 citations