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J. Biol. Chem., Vol. 282, Issue 50, 36230-36239, December 14, 2007

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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^*

Soon-Duck Ha¹, Dennis Ng¹, Steven L. Pelech^¶||, and Sung Ouk Kim²

From the Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, ^¶Kinexus Bioinformatics Corporation, Vancouver, British Columbia V6T 1Z3, and the ^||Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada

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- (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.

Received for publication, September 11, 2007 , and in revised form, October 15, 2007.

^* This work was supported by the Canadian Institute of Health Research (Grant MOP68841 to S. O. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Western Ontario, 1400 Western Rd., Siebens-Drake Research Institute, Rm. 119, London, Ontario N6G 2V4, Canada. Tel.: 519-850-296; Fax: 519-661-2046; E-mail: sung.kim{at}schulich.uwo.ca.

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