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.
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.
Ha
Soon-Duck
SD
Department of Microbiology and Immunology, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, Canada N6G 2V4.
Ng
Dennis
D
Pelech
Steven L
SL
Kim
Sung Ouk
SO
D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000633:toxicity*; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells; D037521:Virulence Factors / Q000633:toxicity*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; C030325:anthrax toxin; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D046988:Proteasome Endopeptidase Complex