Critical Role of the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase-3β 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-α (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 3β (GSK3β) 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/GSK3β signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation. 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-α (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 3β (GSK3β) 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/GSK3β signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation. Bacillus anthracis is a Gram-positive spore forming bacterium and systemic infection of B. anthracis is often fatal when inhaled spores germinate inside the host (1Dixon T.C. Meselson M. Guillemin J. Hanna P.C. N. Engl. J. Med. 1999; 341: 815-826Crossref PubMed Scopus (882) Google Scholar). The virulence of B. anthracis is primarily attributed to two secreted exotoxins, lethal toxin (LeTx) 3The abbreviations used are:LeTxlethal toxinPAprotective antigenLFlethal factorEFedema factorMAPKmitogen-activated protein kinaseMEKmitogen-activated protein kinase/extracellular signal-regulated kinase kinaseCFSEcarboxyfluorescein succinimidyl esterNALP1bNACHT-leucine-rich repeat and pyrin domain-containing protein 1bChk1checkpoint kinase 1TNFtumor necrosis factor-αLPSlipopolysaccharidePI3Kphosphatidylinositol 3-kinaseGSK3βglycogen synthase kinase 3βJNKc-Jun N-terminal kinaseERKextracellular signal-regulated kinasePBMCperipheral blood mononuclear cellMOPS4-morpholinepropanesulfonic acidPIpropidium iodideFACSfluorescence-activated cell sortingSBSB202190LyLY294002Aktmyrmyristoylated Akt. 3The abbreviations used are:LeTxlethal toxinPAprotective antigenLFlethal factorEFedema factorMAPKmitogen-activated protein kinaseMEKmitogen-activated protein kinase/extracellular signal-regulated kinase kinaseCFSEcarboxyfluorescein succinimidyl esterNALP1bNACHT-leucine-rich repeat and pyrin domain-containing protein 1bChk1checkpoint kinase 1TNFtumor necrosis factor-αLPSlipopolysaccharidePI3Kphosphatidylinositol 3-kinaseGSK3βglycogen synthase kinase 3βJNKc-Jun N-terminal kinaseERKextracellular signal-regulated kinasePBMCperipheral blood mononuclear cellMOPS4-morpholinepropanesulfonic acidPIpropidium iodideFACSfluorescence-activated cell sortingSBSB202190LyLY294002Aktmyrmyristoylated Akt. and edema toxin, and an exterior capsule, encoded in two large plasmids (2Green B.D. Battisti L. Koehler T.M. Thorne C.B. Ivins B.E. Infect. Immun. 1985; 49: 291-297Crossref PubMed Google Scholar, 3Mikesell P. Ivins B.E. Ristroph J.D. Dreier T.M. Infect. Immun. 1983; 39: 371-376Crossref PubMed Google Scholar). The capsule comprises poly-d-glutamic acid, which protects bacteria from phagocytosis by the host immune cells and contributes to bacterial dissemination (4Drysdale M. Heninger S. Hutt J. Chen Y. Lyons C.R. Koehler T.M. EMBO J. 2005; 24: 221-227Crossref PubMed Scopus (139) Google Scholar). LeTx and edema toxin are binary A:B toxins comprising protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. PA is a molecular transporter allowing receptor-mediated entry and release of LF or EF into the cytosol. PA binds to either of two surface receptors: anthrax receptor 1 (also known as the tumor endothelial marker 8) and anthrax receptor 2 (also known as the capillary morphogenesis gene-2). Anthrax receptor 1 is expressed in high levels in macrophages, endothelial cells and several tumor cells (5Bradley K.A. Mogridge J. Mourez M. Collier R.J. Young J.A. Nature. 2001; 414: 225-229Crossref PubMed Scopus (750) Google Scholar, 6Bonuccelli G. Sotgia F. Frank P.G. Williams T.M. de Almeida C.J. Tanowitz H.B. Scherer P.E. Hotchkiss K.A. Terman B.I. Rollman B. Alileche A. Brojatsch J. Lisanti M.P. Am. J. Physiol. 2005; 288: C1402-C1410Crossref PubMed Scopus (95) Google Scholar, 7Rmali K.A. Al-Rawi M.A. Parr C. Puntis M.C. Jiang W.G. Int. J. Mol. Med. 2004; 14: 75-80PubMed Google Scholar); whereas, anthrax receptor 2 is widely distributed in human tissues (8Scobie H.M. Rainey G.J. Bradley K.A. Young J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5170-5174Crossref PubMed Scopus (521) Google Scholar). EF has adenylate cyclase activity (9Leppla S.H. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 3162-3166Crossref PubMed Scopus (760) Google Scholar), whereas LF is a zinc metalloprotease that cleaves and inactivates the N-terminal end of the mitogen-activated protein kinase (MAPK) kinases (MEK) 1 to 7, except MEK5, resulting in the inactivation of most their downstream signaling cascades. Both LF and EF cause severe defects in immune responses and contribute proliferation and dissemination of B. anthracis in the host (10Li Y. Sherer K. Cui X. Eichacker P.Q. Expert. Opin. Biol. Ther. 2007; 7: 843-854Crossref PubMed Scopus (14) Google Scholar, 11Tournier J.N. Quesnel-Hellmann A. Cleret A. Vidal D.R. Cell Microbiol. 2007; 9: 555-565Crossref PubMed Scopus (64) Google Scholar). lethal toxin protective antigen lethal factor edema factor mitogen-activated protein kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase carboxyfluorescein succinimidyl ester NACHT-leucine-rich repeat and pyrin domain-containing protein 1b checkpoint kinase 1 tumor necrosis factor-α lipopolysaccharide phosphatidylinositol 3-kinase glycogen synthase kinase 3β c-Jun N-terminal kinase extracellular signal-regulated kinase peripheral blood mononuclear cell 4-morpholinepropanesulfonic acid propidium iodide fluorescence-activated cell sorting SB202190 LY294002 myristoylated Akt lethal toxin protective antigen lethal factor edema factor mitogen-activated protein kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase carboxyfluorescein succinimidyl ester NACHT-leucine-rich repeat and pyrin domain-containing protein 1b checkpoint kinase 1 tumor necrosis factor-α lipopolysaccharide phosphatidylinositol 3-kinase glycogen synthase kinase 3β c-Jun N-terminal kinase extracellular signal-regulated kinase peripheral blood mononuclear cell 4-morpholinepropanesulfonic acid propidium iodide fluorescence-activated cell sorting SB202190 LY294002 myristoylated Akt Monocytes and macrophages are key innate immune cells and likely the first immune cells encountering the spores and germinating bacteria (12Cote C.K. Rea K.M. Norris S.L. van Rooijen N. Welkos S.L. Microb. Pathog. 2004; 37: 169-175Crossref PubMed Scopus (66) Google Scholar, 13Cote C.K. Van Rooijen N. Welkos S.L. Infect. Immun. 2006; 74: 469-480Crossref PubMed Scopus (123) Google Scholar, 14Hu H. Sa Q. Koehler T.M. Aronson A.I. Zhou D. Cell Microbiol. 2006; 8: 1634-1642Crossref PubMed Scopus (66) Google Scholar). LeTx induces rapid necrosis-like cell death of macrophages prepared from certain strains of inbred mice (15Friedlander A.M. J. Biol. Chem. 1986; 261: 7123-7126Abstract Full Text PDF PubMed Google Scholar, 16Welkos S.L. Keener T.J. Gibbs P.H. Infect. Immun. 1986; 51: 795-800Crossref PubMed Google Scholar, 17Kim S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 18Muehlbauer S.M. Evering T.H. Bonuccelli G. Squires R.C. Ashton A.W. Porcelli S.A. Lisanti M.P. Brojatsch J. 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Duesbery N.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), H. L. Chen J. 2006; PubMed Scopus Google Scholar), and F. M. L. C. J. Med. 2005; PubMed Scopus Google Scholar, H. J. 2005; PubMed Scopus Google Scholar, Infect. Immun. 2005; PubMed Scopus Google Scholar), which contribute to the host immune the signaling of cell proliferation by LeTx and in the of anthrax This study on the of LeTx on cell proliferation. LeTx induced cell cycle arrest in G0-G1 phase key cell cycle progress cyclin and checkpoint kinase 1 MEK1 in human monocytic cell LF inside cells activity and tumor necrosis factor-α (TNF) production in response to a bacterial lipopolysaccharide Recovery from the LF activity and the required cell which was through response of THP-1 cells by the phosphatidylinositol 3-kinase signaling pathway. of by cells with LeTx or a protected cell cycle arrest and recovery from cellular LeTx Cell and human monocytic cell THP-1 and cells in and 1 in the of LF and PA prepared in the as J. S. Collier R.J. 37: PubMed Scopus Google Scholar, C.J. Collier R.J. 1999; PubMed Scopus Google Scholar). Akt inhibitor and inhibitor from inhibitor and inhibitor was from and MEK1 of and from Cell The the of MEK1 was from and and cyclin D1 and LF from and respectively. of and peripheral blood mononuclear cells from blood from with of and on of the a to 1 cells into and the was with and with of mouse peritoneal macrophages, mice of before the of peritoneal macrophages. from mice by of into peritoneal and by with a through a cell and in a of macrophages from mice as J. Biol. PubMed Scopus Google Scholar), except cells with for Cell and cell and as S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). cells in cell 2 1 1 1 1 and and on Cell by the for These in by with for with and an cell from THP-1 cells LeTx of LF and of PA for exposure and Cell was as on the on the the cellular was to the of was by and the to the the for cyclin and for cyclin and for cyclin and for cyclin and for and for and Cell and of by carboxyfluorescein succinimidyl ester and propidium iodide on a cell proliferation by cells with of 1 for and was on an for 2 with of and for by cells the by of with and cell by and in of and of of the cell was in a The and the of to cell and and and and infection as S.O. S. S. Beutler B. Han J. 2007; PubMed Scopus Google Scholar). active myristoylated Akt and dominant Akt in cells the was by for for and for for of was and through a THP-1 cells of 1 with of and in The for and into the cells by protein infection and with the LeTx for cell cycle and human mutant cyclin was by a J.A. F. C.J. PubMed Scopus Google with the and the resulting into the The was by The transfection of plasmids was by in THP-1 cell and mutant cyclin D1 cells by LeTx Cell that LeTx inhibits proliferation and of immune cells A. Mogridge J. Cell Microbiol. 2005; 7: PubMed Scopus Google Scholar, H. L. Chen J. 2006; PubMed Scopus Google Scholar, Infect. Immun. 2005; PubMed Scopus Google Scholar). the of cell cycle arrest in the human monocytic cells lines and of cells brief exposure of LeTx LF and PA for was for by the of in cells. LeTx cell proliferation of and THP-1 cells for to 2 and Cell cycle showed that of cells in G0-G1 phase of cell cycle was whereas in and phase in THP-1 and cells LeTx a of and through MEK1 signaling in the LeTx-induced cell cycle arrest, cell in THP-1 cells. protein levels of cyclin D1 and most by LeTx Both protein and levels of cyclin D1 in and whereas, the in protein and levels of and an LeTx and The rapid of cyclin D1 in and protein levels was likely to by LF the levels and the of the and It is that cyclin D1 was by cells with the inhibitor or with proteasome-mediated degradation-defected mutant cyclin D1 to LeTx-induced cyclin D1 down-regulation cyclin D1 levels in cells with the inhibitor with the in and cells LeTx cleaves the N-terminal end of and inhibits most downstream of cause cell cycle arrest in THP-1 cells. of the MEK1 inhibitor for caused of cells G0-G1 phase and prevented into whereas, the inhibitor SB202190 on phase prevented cells phase of and cell cycle inhibitor on cell cycle progress of THP-1 cells. These results indicate that LeTx cells phase and phase by and respectively. results in cells. THP-1 cells with or induced down-regulation of cyclin D1 and that the down-regulation of cyclin D1 and by LF was in through MEK1 In to cyclin levels of cyclin by and by or LeTx on levels of cyclin and cyclin of and TNF in to by LeTx in that LF inside cells and cleaves MEK1 for in cell cells D. J. M.A. Han J. S.O. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). the of LF activity in non-proliferating to LeTx for and cells in for to and cells with for and TNF production was a TNF as A. X. Van C. X. D. M. C. M. P. B. Beutler B. PubMed Scopus Google and N-terminal cleavage was the cell a brief exposure of LeTx MEK1 and prevented TNF production in responses to are a of and cells in and that cells in 1 and in of the cells and in and in non-proliferating macrophages, mouse peritoneal macrophages from mice macrophages S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google and with MEK1 was by a brief exposure of LeTx for the by when cells by TNF production in response to was for the Cell by LeTx in the of in of LeTx is in non-proliferating cells. LeTx cell cycle arrest, the of LeTx be in cells. However, when MEK1 N-terminal cleavage and TNF production in response to in THP-1 MEK1 and TNF production to levels in LeTx on LF inside cells was LF was of a LeTx cell cycle arrest by LeTx was before In THP-1 cells cell cycle before the when LF was by and TNF production in response to was Cell cycle arrest was the and to levels of a LeTx These results indicate that THP-1 cells cell cycle in the of with LeTx from Cell by LeTx through of cells adaptively adjusted to LeTx and cell cycle in the of cells to in the of LeTx cells to LeTx-induced cell cycle arrest, cells for with LeTx and 2 the with of cells and by LeTx in 2 cells to cell cycle arrest by a the to cell cycle arrest was to of cells to LeTx into cells or N-terminal cleavage and phosphorylation with results in and basal phosphorylation in which and by LeTx These results indicate defects of LeTx cells in LF into the and in cells that cell cycle arrest Mol. Cell Biol. 2001; PubMed Scopus Google Scholar). such as LY294002 the in THP-1 cells on cell cycle cells with the recovery from cell cycle phase was prevented of LeTx results by inhibitor which is a downstream protein of was by LeTx induced Akt phosphorylation the activating in 2 of LeTx and Akt in which was The Akt phosphorylation to be through or was to the Akt that Akt is in cell cycle in the of cell cycle progress in THP-1 cells with LeTx for 2 by or with the Akt inhibitor or in cells with Akt mutant Akt an the or mutant Akt myristoylated The entry for which sorting of cells J. S. M. Van L. M. 2004; PubMed Scopus Google Scholar). THP-1 cells with or cells showed recovery or whereas, cells with from cell cycle arrest cells with protein levels of cyclin D1 and in LeTx and the recovery of cyclin D1 and in levels and protein levels These results indicate that of and Akt in response to LeTx overrode cell cycle arrest induced by which is required for recovery from cellular LeTx of by Akt D1 and from LeTx-induced Cell the and by on or respectively. Akt by LeTx phosphorylation of and protects LeTx-induced cell cycle with a for in THP-1 and the phosphorylation was 2 LeTx The phosphorylation was by or Furthermore, THP-1 cells with LeTx with the GSK3-specific inhibitor protected cells from cell cycle arrest induced by LeTx was to cell cycle through cyclin D1 J.A. M. C.J. PubMed Scopus Google Scholar). cyclin D1 on and proteasome-mediated by Akt cyclin THP-1 cells or with LeTx for and with the GSK3-specific inhibitor for to levels of cyclin D1 to as as 1 of the whereas MEK1 was by LF D1 protein was with the by a inhibitor However, cyclin D1 levels by either These results indicate that by Akt in cyclin D1 and overrode cell cycle arrest induced by LeTx in THP-1 cells. Cell for Recovery from LeTx intoxication was in non-proliferating and peritoneal macrophages It for THP-1 cells to from LeTx intoxication and their cell cycle 2 of LeTx is that or facilitating cell cycle recovery in or recovery from LeTx THP-1 cells by LeTx to cell cycle recovery and recovery of MEK1 cleavage by LF was MEK1 was of LeTx whereas cells to from MEK1 cleavage of cyclin prevented LeTx-induced cell cycle arrest and induced recovery from LeTx THP-1 cells with cyclin from LeTx-induced MEK1 cleavage and suppression of TNF production in response to cells of D1 and LeTx Recovery in cell cycle progress recovery from LeTx intoxication in cells. macrophages in for several in the of factor or which M. J. A. J. 2004; PubMed Scopus Google Scholar). LeTx cyclin D1 and induced cell cycle arrest in cells of a LeTx cells from MEK1 cleavage and cyclin D1 in cells with whereas cells with GSK3-specific inhibitor cyclin D1 protein levels and recovery from MEK1 cleavage In TNF production to of levels of a LeTx In cells with TNF production was of a LeTx In cells with TNF to of levels in 2 a LeTx These results that the signaling is required for recovering from cellular LeTx intoxication and cell cycle progress by cyclin D1 recovery from the LeTx was to cell cycle progress in monocytic cell lines A. Mogridge J. Cell Microbiol. 2005; 7: PubMed Scopus Google Scholar), H.M. M. S.H. Duesbery N.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), cells H. L. Chen J. 2006; PubMed Scopus Google Scholar), and cells F. M. L. C. J. Med. 2005; PubMed Scopus Google Scholar, H. J. 2005; PubMed Scopus Google Scholar, Infect. Immun. 2005; PubMed Scopus Google Scholar). This study showed that LeTx prevented entry of phase human monocytic cell lines through of LeTx to be widely expressed (8Scobie H.M. Rainey G.J. Bradley K.A. Young J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5170-5174Crossref PubMed Scopus (521) Google Scholar); cell cycle arrest by LeTx is likely to in a of cell that basal activity for proliferation. was to be required for cell cycle progress from to phase through S. J. 2007; PubMed Scopus Google Scholar). and that LeTx cyclin D1 and protein levels likely through of their and the cyclin D1 a C. J. G. N. D. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), is that basal required for levels of cyclin D1 by such as and in THP-1 cells. the MEK1 inhibitor which and protein levels of cyclin D1 and and of cyclin by is cells to cyclin through receptor-mediated for proliferation C. T.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The of cyclin D1 and for from and and of phase through activating kinases and has as B.D. Cell Biol. 2005; PubMed Scopus Google Scholar). The down-regulation of by LeTx was likely through activity and was to a key in the checkpoint in response K.A. 2007; 6: PubMed Scopus Google Scholar). of by of a resulting in of kinases Y. C. H. PubMed Scopus Google Scholar). was to be required for cell cycle progress for and in cell N. C. S. Cell Cycle. 2004; PubMed Scopus Google Scholar, J. X. Proc. Natl. Acad. Sci. U. S. A. 2006; PubMed Scopus Google Scholar), cellular for be various and cell G. Rainey EMBO J. 2003; PubMed Scopus Google Scholar, Chen J. H. S. S. H. Mol. Ther. 2003; PubMed Scopus Google Scholar). The inhibitor cell cycle progress in THP-1 cells and of cyclin was to cell cycle arrest induced by LeTx that basal activity is required for cell cycle progress in THP-1 cells. that LF inside cell and cleaves for a brief exposure of LeTx in cell cells D. J. M.A. Han J. S.O. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). LeTx was to non-proliferating human or peritoneal macrophages, the MEK1 cleavage and of TNF production in response to as as the cells in LeTx cell is that the LeTx are as non-proliferating cells. However, MEK1 and TNF response to was in LeTx in THP-1 cells In cell cycle of THP-1 cells before of LeTx before MEK1 cleavage was Furthermore, THP-1 cells to THP-1 cells to cell cycle arrest by LeTx This is a of the response to LeTx-induced in macrophages D. J. M.A. Han J. S.O. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: PubMed Scopus Google Scholar). cell lines or primary macrophages from inbred mice rapid by LeTx S.L. Keener T.J. Gibbs P.H. Infect. Immun. 1986; 51: 795-800Crossref PubMed Google Scholar, 17Kim S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 2006; PubMed Scopus Google Scholar). These macrophages adaptively to a of LeTx and to of is D. J. M.A. Han J. S.O. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: PubMed Scopus Google Scholar). that to is through down-regulation of two cell death protein and D. J. M.A. Han J. S.O. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). macrophages and are to LeTx-induced S.M. Evering T.H. Bonuccelli G. Squires R.C. Ashton A.W. Porcelli S.A. Lisanti M.P. Brojatsch J. Cell Cycle. 2007; 6: PubMed Scopus Google Scholar, J. J. A. D. C. K. PubMed Scopus Google Scholar, A. Mogridge J. Cell Microbiol. 2005; 7: PubMed Scopus Google Scholar). The response to LeTx-induced cell cycle arrest in THP-1 and U-937 cells was through activating the signaling recovery from cell cycle arrest was a for cellular recovery from the on-going MEK1 cleavage by LF and is LF can active for such a in the cytosol. cellular intoxication of LF in non-proliferating cells that the toxic of LeTx in a B. host that most tissues are and of of LeTx in mice was to MEK1 to in various tissues such as and LeTx was of the was to cell cycle progress through cyclin D1 of the kinase inhibitor and of a of and that is to cyclin D1 in an K. J. Y. S. Am. J. Cell Mol. Biol. PubMed Scopus Google Scholar, N. Y. Y. Mol. Cell Biol. 1999; PubMed Scopus Google and arrest in cells Mol. Cell Biol. 2001; PubMed Scopus Google Scholar). the of cyclin D1 in to phase cell cycle is that the response of THP-1 cells in cell cycle arrest was in through cyclin D1 protein the The of cyclin D1 in cells is H. C.J. Full Text PDF PubMed Scopus Google Scholar), and the rapid is to and proteasome-mediated degradation of cyclin D1 J.A. F. C.J. PubMed Scopus Google Scholar). D1 phosphorylation on was by the J.A. M. C.J. PubMed Scopus Google Scholar), which is phosphorylation on Ser-9 by Akt M. P. D.R. PubMed Scopus Google Scholar). can be that activating or LeTx-induced cell cycle arrest in cells and recovery from a LeTx whereas the which can be in several can be to cells. cellular showed that of or of degradation mutant cyclin D1 protected cell cycle arrest induced by LeTx and recovery from LeTx intoxication and It be that and are and by is that of the of by LeTx and such as and by of signaling in LeTx-induced cell cycle arrest and recovery LeTx has as a key virulence factor in the of causing immune cell cycle arrest, and cell death in host immune cells. These contribute and proliferation of B. anthracis the host. Furthermore, the of the infected bacterial by The fatal are attributed to production and release of anthrax This study showed that LF inside cells and cleaves in an of LF intoxication in cells. The recovery from the of LeTx can be by activating activating the signaling or of can be for for LeTx whereas that the signaling can be to the host. for for and and J. A. for

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