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rdf:type |
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lifeskim:mentions |
umls-concept:C0003175,
umls-concept:C0024432,
umls-concept:C0031621,
umls-concept:C0035820,
umls-concept:C0086982,
umls-concept:C0596311,
umls-concept:C0752313,
umls-concept:C1155873,
umls-concept:C1330957,
umls-concept:C1511545,
umls-concept:C2004454
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pubmed:issue |
50
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pubmed:dateCreated |
2007-12-10
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pubmed:abstractText |
Anthrax lethal toxin (LeTx) is a virulence factor causing immune suppression and toxic shock of Bacillus anthracis infected host. It inhibits cytokine production and cell proliferation/differentiation in various immune cells. This study showed that a brief exposure of LeTx caused a continual MEK1 cleavage and prevented tumor necrosis factor-alpha (TNF) production in response to lipopolysaccharide (LPS) in non-proliferating cells such as human peripheral blood mononuclear cells or mouse primary peritoneal macrophages. In human monocytic cell lines U-937 and THP-1, LeTx induced cell cycle arrest in G0-G1 phase by rapid down-regulation of cyclin D1/D2 and checkpoint kinase 1 through MEK1 inhibition. However, THP-1 cells adaptively adjusted to LeTx and overrode cell cycle arrest by activating the phosphatidylinositol 3-kinase/Akt signaling pathway. Inhibitory Ser-9 phosphorylation of glycogen synthase kinase 3beta (GSK3beta) by Akt prevented proteasome-mediated cyclin D1 degradation and induced cell cycle progress in LeTx-intoxicated THP-1 cells. Recovery from cell cycle arrest was required before recovering from on-going MEK1 cleavage and suppression of TNF production. Furthermore, pretreatment with LeTx or the GSK3-specific inhibitor SB-216763, or transfection with dominant active mutant Akt or degradation-defected mutant cyclin D1 protected cells from LeTx-induced cell cycle arrest, on-going MEK1 cleavage and suppression of TNF production. These results indicate that modulation of phosphatidylinositol 3-kinase/Akt/GSK3beta signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Bacterial,
http://linkedlifedata.com/resource/pubmed/chemical/Bacterial Toxins,
http://linkedlifedata.com/resource/pubmed/chemical/CCND2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Ccnd2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/MAP2K1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Map2k1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Virulence Factors,
http://linkedlifedata.com/resource/pubmed/chemical/anthrax toxin,
http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 beta
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
14
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pubmed:volume |
282
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
36230-9
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:17951252-Animals,
pubmed-meshheading:17951252-Antigens, Bacterial,
pubmed-meshheading:17951252-Bacillus anthracis,
pubmed-meshheading:17951252-Bacterial Toxins,
pubmed-meshheading:17951252-Cyclin D,
pubmed-meshheading:17951252-Cyclin D2,
pubmed-meshheading:17951252-Cyclins,
pubmed-meshheading:17951252-Down-Regulation,
pubmed-meshheading:17951252-G0 Phase,
pubmed-meshheading:17951252-G1 Phase,
pubmed-meshheading:17951252-Glycogen Synthase Kinase 3,
pubmed-meshheading:17951252-Humans,
pubmed-meshheading:17951252-Lipopolysaccharides,
pubmed-meshheading:17951252-MAP Kinase Kinase 1,
pubmed-meshheading:17951252-Macrophages, Peritoneal,
pubmed-meshheading:17951252-Mice,
pubmed-meshheading:17951252-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:17951252-Proteasome Endopeptidase Complex,
pubmed-meshheading:17951252-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:17951252-Signal Transduction,
pubmed-meshheading:17951252-Tumor Necrosis Factor-alpha,
pubmed-meshheading:17951252-U937 Cells,
pubmed-meshheading:17951252-Virulence Factors
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pubmed:year |
2007
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pubmed:articleTitle |
Critical role of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway in recovery from anthrax lethal toxin-induced cell cycle arrest and MEK cleavage in macrophages.
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pubmed:affiliation |
Department of Microbiology and Immunology, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, Canada N6G 2V4.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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