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

Duesbery, Nicholas S.; Webb, Craig P.; Leppla, Stephen H.; Gordon, V M; Klimpel, Kurt R.; Copeland, Terry D.; Ahn, Natalie G.; Oskarsson, M; Fukasawa, Kenji; Paull, K.; Woude, George F. Vande

doi:10.1126/science.280.5364.734

Cited by 958 publications

(766 citation statements)

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“…It involved both B-cell and T-cell zones of lymph nodes and spleen similarly but was also prominent near clusters of bacilli. Lethal toxin interferes with intracellular signaling (23) and may induce apoptosis. Inflammatory response was scant compared with the magnitude of necrosis/apoptosis, but neutrophils were prominent in patients with shorter survival, whereas mononuclear cells (large lymphocytes, immunoblasts, and macrophages) were significantly associated with longer survival.…”

Section: Epidemiological and Clinical Variablesmentioning

confidence: 99%

“…EF acts as an Ca ϩ2 -and calmodulindependent adenylate cyclase which induces edema (22). LF is a metalloprotease that cleaves the amino terminus of MAP kinase kinases 1 and 2 and thus inhibits the intracellular MAPK signal transduction pathway (23), which may favor apoptosis. A sublethal concentration of LF also causes macrophages to produce TNF-␣ and IL-1 (24), which might induce pathologic effects.…”

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confidence: 99%

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Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings

Abramova²,

et al. 2001

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Forty-one cases of documented inhalational anthrax from the Sverdlovsk epidemic of 1979 traced to release of aerosols of Bacillus anthracis at a secret biologic-agent production facility were evaluated by semiquantitative histopathologic analysis of tissue concentrations of organisms, inflammation, hemorrhage, and other lesions in the mediastinum, mediastinal lymph nodes, bronchi, lungs, heart, spleen, liver, intestines, kidneys, adrenal glands, and central nervous system. These data were correlated with clinical, epidemiologic, and demographic data.The patients' courses, with a variable incubation period and short nonspecific course (4 days before hospitalization) with rapid demise (1 day of hospitalization before death), correlated with systemic bacterial infection and lesions. Bacillus anthracis were identified in all cases in which there was no antibiotic treatment or there was treatment for fewer than 21 hours. The lesions that were the most severe and apparently of longest duration were in the mediastinal lymph nodes and mediastinum. There and elsewhere, peripheral transudate surrounded fibrin-rich edema; necrosis of arteries and veins was the most likely source of large hemorrhages displacing tissue or infiltrating tissue, respectively; and apoptosis of lymphocytes was observed. Respiratory function was compromised by mediastinal expansion, large pleural effusions, and hematogenous and retrograde lymphatic vessel spread of B. anthracis to the lung with consequent pneumonia. The central nervous system and intestines manifested similar hematogenous spread, vasculitis, hemorrhages, and edema. These pathologic findings are consistent with previous experimental studies showing transport of inhaled spores to mediastinal lymph nodes, where germination and growth lead to local lesions and systemic spread, with resulting edema and cell death, owing to the effects of edema toxin and lethal toxin. The identification of the vascular lesions as a basis for the prominent hemorrhages is a novel observation for human inhalational anthrax.

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Section: Epidemiological and Clinical Variablesmentioning

confidence: 99%

mentioning

confidence: 99%

Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings

Abramova²,

et al. 2001

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“…To determine the activation levels of MAP kinase, we have used Western blots in conjunction with antibodies speci®c for the dual phosphorylated active MAP kinases (p44 ERK1 and p42 ERK2) (Duesbery et al, 1998;Majeti et al, 1998;Yablonski et al, 1998). Densitometric scanning was used to quantitate the activation levels of MAP kinases (active ERK1,2) in relation to the amount of MAP kinase proteins present.…”

Section: Grb2 Protein Inhibition Led To Inactivation Of Map Kinase Inmentioning

confidence: 99%

“…Rabbit antibodies speci®c for MAP kinase and active ERK1,2 proteins were purchased from Oncogene and New England Biolabs, respectively. The latter antibody recognizes only active, but not inactive, ERK1,2 (Duesbery et al, 1998;Majeti et al, 1998;Yablonski et al, 1998). Anti-mouse or anti-rabbit secondary antibodies conjugated with horseradish peroxidase were obtained from Amersham.…”

Section: Antibodiesmentioning

confidence: 99%

Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells

Tari

Hung

et al. 1999

Oncogene

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“…In this regard, it has been shown that intracellular pathogens such as Yersinia, which infect macrophages, have virulence factors that deactivate macrophages through p38 inhibition, preventing TNF secretion [37]. Bacillus antracis releases the anthrax lethal toxin, a major virulence factor that proteolytically cleaves MKK1 and MKK2, inactivating them and leading to inhibition of the ERK signal transduction pathway in macrophages [38]. Moreover, Leishmania donovani evade the activation of p38, JNK and ERK during infection of naive macrophages [39].…”

Section: Discussionmentioning

confidence: 99%

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

Alcaide

Fresno

2004

Eur J Immunol

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Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function by a Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983-4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-+ in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK) activation.

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

Cited by 958 publications

References 20 publications

Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings

Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings

Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

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