Peer-Reviewed Journal Details
Mandatory Fields
Naughton, R,Quiney, C,Turner, SD,Cotter, TG;
2009
August
Official Journal of The Leukemia Society of America
Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway
Validated
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Optional Fields
Bcr-Abl PI3k/Akt pathway NADPH oxidase protein phosphatase CHRONIC MYELOGENOUS LEUKEMIA PROTEIN PHOSPHATASE 2A SMALL GTPASE RAC REACTIVE OXYGEN NADPH OXIDASES HYDROGEN-PEROXIDE TYROSINE KINASE ACTIVATION CELLS INHIBITION
23
1432
1440
Bcr-Abl causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells. In this study, inducible expression of Bcr-Abl in TonB. 210 cells is associated with increased production of intracellular reactive oxygen species (ROS), which is thought to play a role in survival signaling when generated at specific levels. Elevated ROS in Bcr-Abl-expressing cells were found to activate PI3k/Akt pathway members such as Akt and GSK3 beta as well as downstream targets beta-catenin and Mcl-1. The activation of these proteins was inhibited by the flavoprotein inhibitor diphenyleneiodonium, which is commonly used to inhibit NADPH oxidase (Nox). This indicated that increased ROS might be related to increased activity of one member of the Nox family. Knock-down experiments using siRNA suggest that Nox-4 is the main source of increased ROS following Bcr-Abl expression. We showed that Bcr-Abl-induced ROS could also increase survival pathway signaling through redox inhibition of PP1 alpha, a serine threonine phosphatase that negatively regulates the PI3k/Akt pathway. Overall our results demonstrate that Bcr-Abl expression increases Nox-4-generated ROS, which in turn increases survival signaling through PI3k/Akt pathway by inhibition of PP1a, thus contributing to the high level of resistance to apoptosis seen in these Bcr-Abl-expressing cells. Leukemia (2009) 23, 1432-1440; doi:10.1038/leu.2009.49; published online 19 March 2009
DOI 10.1038/leu.2009.49
Grant Details