Date of Award
2008
Degree Type
Thesis
Degree Name
Master of Science
Program
Microbiology and Immunology
Supervisor
Dr. Sung Kim
Second Advisor
Dr. Ewa Cairns
Third Advisor
Dr. John McCormick
Abstract
Lethal toxin (LeTx) is a critical virulence factor of B. anthracis causing immune suppression and toxic shock of the infected host. It inhibits cytokine production and cell proliferation/differentiation in various immune cells. In the present study, I demonstrated that a brief exposure to LeTx caused a continual MEK1 cleavage and prevented TNF-ce production 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 Go-Gi 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 PI3K/Akt signaling pathway. Activated Akt inhibited GSK3 and prevented proteasome-mediated cyclin D1 degradation in LeTx-intoxicated THP-1 cells. Recovery from cell cycle arrest was required before recovering from on-going MEK1 cleavage and suppression of TNF-a production. This study demonstrated that modulation of PI3K/Akt/GSK3 signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation.
Recommended Citation
Ng, Dennis Y.M., "Critical role of PI3-K/Akt/GSK-3(5 signaling pathway in recovery from anthrax lethal toxin-induced cell cycle arrest and MEK cleavage in macrophages" (2008). Digitized Theses. 4134.
https://ir.lib.uwo.ca/digitizedtheses/4134